Assessing the Effectiveness of Stabilized Cysteamine 5% Cream Compared to Hydroquinone 4%/Ascorbic Acid 3% Combination Cream in Treating Acne-induced Post-inflammatory Hyperpigmentation: A Randomized, Controlled Study

J Clin Aesthet Dermatol. 2024;17(4):37–41.

by Koorosh Ahmadi, MD; Amir Miri, MD; Zeinab Bizaval, MD; Mozhdeh Sepaskhah, MD; Sara Ranjbar, MSc;
Zahra Bagheri, PhD; and Behrooz Kasraee, MD

Drs. Ahmadi, Miri, and Bizaval are with the Department of Dermatology and School of Medicine at Shiraz University of Medical Sciences in Shiraz, Iran. Dr. Sepaskhah is with the Department of Dermatology, School of Medicine, and Molecular Dermatology Research Center at Shiraz University of Medical Sciences in Shiraz, Iran. Ms. Ranjbar is with the Molecular Dermatology Research Center at Shiraz University of Medical Sciences in Shiraz, Iran. Dr. Bagheri is with the Department of Biostatistics and School of Medicine at Shiraz University of Medical Sciences in Shiraz, Iran. Dr. Kasraee is with Scientis SA in Geneva, Switzerland.

FUNDING: This article was financially supported by a grant from the vice chancellery for research affairs at Shiraz University of Medical Sciences.

DISCLOSURES: Dr. Kasraee is a shareholder of Scientis SA in Switzerland. All other authors report no conflicts of interest relevant to the contents of this article.

ABSTRACT: Objective. Postinflammatory hyperpigmentation (PIH) is a common sequela of acne vulgaris. Topical treatment with hydroquinone is the standard treatment, but may be associated with complications. Cysteamine is a relatively safe depigmenting agent with an observed depigmenting effect. We designed this study to assess the efficacy of a cysteamine 5% cream in treating acne-induced PIH.

Methods. Twenty-eight out of 32 participants finalized this investigator-blind, randomized, and controlled trial (registered in Iranian Registry of Clinical Trials [IRCTID: IRCT20140212016557N5]). We randomized the patients to apply either cysteamine 5% or hydroquinone 4%/ascorbic acid 3% (HC) cream. Postacne hyperpigmentation index (PAHPI) and melanin index were the assessment measures after four months of treatment. We evaluated the quality of life by the Dermatology Life Quality Index (DLQI) questionnaire.

Results. Both cysteamine and HC cream significantly decreased the PAHPI score and melanin index of acne-induced PIH patients (p<0.05). The decrease in PAHPI score and melanin index were not significantly different in treatment groups after four months (p>0.05). Quality of life ameliorated significantly only with cysteamine treatment. However, no significant change in quality of life was observed between groups.

Limitations. Limitations of our study include the relatively small sample size and absence of follow-up.

Conclusion. Cysteamine cream is an effective treatment of post-acne PIH, with similar efficacy to the accepted treatment of PIH, i.e., hydroquinone cream.

Keywords: Acne vulgaris, hyperpigmentation, drug therapy, cysteamine, hydroquinone, ascorbic acid, administration, topical


Acne vulgaris is a highly prevalent skin disease that causes a significant disease burden.1 About 60 percent of acne patients experience postinflammatory hyperpigmentation (PIH).2 Both active acne lesions and PIH are troublesome for the patients. PIH is especially a troublesome for individuals with darker skin tones.3 Acne-induced PIH causes embarrassment in over half of the affected patients.4 Acne complicated with PIH affects the patient’s quality of life more than acne alone.5 Although several medications and modalities have been tested, the management of acne-induced PIH is a challenge that dermatologists regularly encounter.6 

Topical medications are the first-line treatment for acne-induced PIH.6 Topical treatments used for PIH due to other causes have been used in acne-induced PIH with different success rates, including topical hydroquinone, retinoid, chemical peels, azelaic acid, kojic acid, and licorice extract.6 Overproduction or abnormal distribution of melanin after inflammation is the pathogenesis of PIH.8 Therefore, the treatment of PIH relies on the treatment of melanogenesis.

Cysteamine is a non-melanocytotoxic, non-mutagenic depigmenting agent that has been proven to have depigmenting effects in guinea pigs and humans.9 Another study showed superior depigmenting activity of cysteamine over placebo in treating epidermal melasma.10 

Considering the mechanism of action of cysteamine, this agent could be a potential treatment for PIH, including acne-induced PIH. However, this effect has not been assessed in a clinical trial. Therefore, we designed this clinical study to assess the therapeutic effect of cysteamine for acne-induced PIH and compare it with hydroquinone efficacy.  


We conducted this parallel, investigator-blind, 1:1 randomized controlled clinical trial (IRCTID: IRCT20140212016557N5) in a dermatology clinic. The institutional review board confirmed the appropriateness of the study protocol. We included patients between 14 and 40 years of age who had no active inflammatory acne lesions after receiving any kind of anti-acne treatment. The patients receiving any depigmenting agent two months before being recruited in the study, patients with a history of hypersensitivity to ingredients of either drug, and pregnant or lactating patients were excluded. 

Due to the lack of a similar study assessing cysteamine cream in treating acne postinflammatory hyperpigmentation, the study was planned as a pilot one, and the sample size was determined as 50 cases. 

We used permuted block randomization (block size 4) to randomly allocate the patients in the treatment groups. An author (M.S.) performed this randomization by a random allocation software. Each group contained 25 patients, and at the end of the study, 13 participants in the cysteamine group and 15 participants in the HC group were analyzed (Figure 1).

The authors that assessed the therapeutic responses K.A., A.M., and Z.B.) were not involved in generating the random allocation sequence and assigning the patients to the treatment groups.

The first group of patients applied cysteamine 5% cream (Scientis Pharma, Switzerland) on the acne-induced PIH lesions for 15 minutes (the recommendation of manufacturer for use of cysteamine cream) at night for four months. The second group applied hydroquinone 4%/ascorbic acid 3% combination (HC) cream on the face, starting from two hours every night increasing to overnight in 7 to 10 days and continuing for four months. An expert pharmacist combined hydroquinone powder (Merck, Germany), ascorbic acid powder (Merck, Germany), and vanishing cream (Rosiran™, Minoo Pharmaceutical Co., Iran) to prepare the HC cream. Hydroquinone and ascorbic acid powders are active ingredients.

The creams were packed in identical tubes labeled by the patient number. Despite the resemblance of the creams, the different application instructions prevented the blindness of participants. Nevertheless, the investigator was blind to the type of medication that each patient applied. The patients were assessed at baseline and the fourth month of treatment. 

The clinical therapeutic response was a decrease in postacne hyperpigmentation index (PAHPI) (primary outcome measure). In the PAHPI scoring system, weighted scores of the size, intensity, and number of PIH lesions are used to calculate the score. The PAHPI score ranges from 6 to 22.11

Also, the melanin index was measured using SkinColorCatch (Delfin Technologies, Finland). The melanin index of 10 post-acne hyperpigmented macules and four points of the surrounding non-pigmented skin were measured, and subtraction of the average of these measures was considered the melanin index.

The patients evaluated the improvement pigmentation in the fourth-month visit using patient’s global assessment (PGA): In this five-point score, the patient evaluates the change of PIH from worse to marked improvement. 

Before beginning and after completing the study, we evaluated the participants quality of life using the Persian version of the Dermatology Life Quality Index (DLQI) validated previously.12 

The potential side effects of the medications (erythema, pruritus, burning sensation, irritation, hypo- and hyperpigmentation) were assessed in follow-up sessions.

The medical research ethics committee of Shiraz University of Medical Sciences approved the proposal (Ethical code: IR.SUMS.REC.1397.947). We considered the ethical principles of the Helsinki Declaration of 1975. The patients were informed about the benefits and disadvantages of both treatments and were recruited into the study after signing the written informed consent.

Version 22 of SPSS software was used to analyze data. The description of the quantitative and qualitative variables was expressed by mean ± standard deviation and relative frequency, respectively. 

Due to some loss to follow-up among patients in treatment groups (18.7% in the cysteamine group and 16/6% in the HC cream group), the analysis of data was conducted based on both per-protocol (PP) and intention-to-treat (ITT) approaches. Multiple imputation method was used for intention-to-treat analysis.

The therapeutic effects of treatments in each treatment group were examined by paired-sample t-test. In order to compare the clinical response rate (PAHPI), melanin index, PAHPI, and DLQI between the two groups, the delta score of each variable (Difference of outcome variables before and after treatment) was computed. Then, two independent sample t-test was applied for the comparison. In addition, considering the ordinal nature of the patient’s global assessments, this variable was compared by the Mann-Whitney test between the groups. 


Thirty-four patients were recruited, and 28 completed this study (Figure 1). The patients’ baseline features are demonstrated in Table 1.

The results of the paired-samples t-test for assessing the effects of each treatment separately and the results of the independent-samples t-test for comparing two treatment groups are presented in Table 2. Each analysis is shown based on both intention-to-treat and per-protocol approaches. Both cysteamine and HC cream significantly reduced the PAHPI score and melanin index of acne-induced PIH patients in ITT and PP approaches (Table 2). 

Based on ITT and PP approaches, no significant decrease was observed in delta scores of PAHPI and melanin index between the two treatment groups after four months of treatment (Table 2).

Quality of life improved significantly after treatment with cysteamine, but the improvement was not significant after HC cream therapy (Table 2). Meanwhile, the difference in improvement of DLQI between the treatment groups was not statistically significant (Table 2).

Post-treatment patient global assessment (Month 4) was 3.46±0.87 in the cysteamine group and 4.07±1.03 in the HC cream group and was not different between groups (p=0.068).

Treatment side effects were encountered in 46.7 percent of cysteamine-treated patients and 33.3 percent of HC cream-treated patients (p=0.358). The side effects included erythema in both groups, dryness and pruritus in the HC group, and burning and scaling in the cysteamine group. 


This research demonstrated that topical cysteamine may be as effective and safe as topical hydroquinone 4%/ascorbic acid 3% combination cream in treating post-acne PIH.

Topical treatment is considered the first-line treatment of post-acne PIH.6 Although topical hydroquinone is regarded as the gold standard treatment of PIH, the safety of this agent is questioned due to the risk of irritation, exogenous ochronosis, and increased cancer risk.15

Some other topical medications are proposed as PIH treatment, including kojic acid, topical retinoids, and azelaic acid.16–18

Cysteamine is one of the newly emerging depigmenting agents with non-melanocytotoxic and non-mutagenic properties.9,19 Depigmenting effects of cysteamine are confirmed in several clinical trials. Most of these studies evaluated the effectiveness of cysteamine in treating melasma.20, 21 Cysteamine was superior22 or equally effective compared to topical hydroquinone combinations in the management of melasma.21 Also, the success rate of topical cysteamine was similar to tranexamic acid mesotherapy.23 In addition, topical cysteamine was studied in treating solar lentigo.24 

Topical cysteamine was effective in a case of PIH refractory to the triple combination of hydroquinone, corticosteroids, and retinoids.25

Based on our information, no clinical trial assessed the effectiveness of topical stabilized cysteamine in treating PIH, including post-acne PIH. Both cysteamine and HC cream were effective in treating post-acne PIH in our study. These treatments did not demonstrate significantly different effectiveness. The adverse effects of both treatments were tolerable, and no significant difference was revealed between cysteamine and HC application. The patients expressed a similar therapeutic response to cysteamine and HC cream. We recognize that the limitation of our study is the relatively small sample size and absence of follow-up. 


The stabilized cysteamine cream evaluated in our study was demonstrated to be an effective treatment of acne-induced PIH, with similar efficacy to the accepted and standard treatment of PIH, i.e., hydroquinone cream. 


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