Ingredients to Treat Post-Inflammatory Hyperpigmentation in Acne

Getting acne under control can be a slow and challenging process; unfortunately, once the acne improves it can be even more difficult to treat the post-inflammatory hyperpigmentation often left behind for many patients. Post-inflammatory hyperpigmentation is the result of excess melanin deposition in response to skin inflammation or injury; in other words, it is the ‘dark spot’ that remains long after the acne lesion has gone.^[1] Post-inflammatory hyperpigmentation can occur in all skin types. However, it disproportionately affects patients with medium-dark skin tones, especially Fitzpatrick skin phototypes III/IV-VI, or those with skin of color.^[1–3] Skin of color is used as a term to identify individuals with darker skin than Caucasians, and includes individuals of many different backgrounds and/or races, including, but not limited to: African American, Hispanic/Latino, Asian, Native American, Pacific Islander, Middle Eastern, African, or mixed.^[4] Epidemiological studies show that post-inflammatory hyperpigmentation is one of the most frequently cited reasons individuals with skin of color visit a dermatologist.^[2,3] 

Patients may think post-inflammatory hyperpigmentation is a type of scar; however, post-inflammatory hyperpigmentation is not permanent. First-line therapy for post-inflammatory hyperpigmentation typically includes photoprotection combined with a topical depigmenting agent, such as hydroquinone.^[3] In addition to hydroquinone, there are a number of other ingredients used to treat hyperpigmentation including mequinol, retinoids, azelaic acid, kojic acid, ascorbic acid, niacinamide, and licorice extracts.^[3,5] It is important to be aware of the associated potential adverse effects of these treatments, particularly for those individuals with medium-dark skin tones or skin of color. 

Photoprotection

Photoprotection plays an integral role in the management of post-inflammatory hyperpigmentation.^[3] Patients with medium-dark skin tones may be especially prone to sunscreen avoidance for several reasons including: 

• a low propensity to sunburn easily, falsely minimizing the necessity for photoprotection^[3,6]
• the white cast left behind by many sunscreen products is especially apparent on medium-dark skin tones and may not be considered attractive 

The important role of sunscreen in decreasing the darkening effects of ultraviolet (UV) radiation on already hyperpigmented skin should be emphasized when caring for patients with post-inflammatory hyperpigmentation.^[3] Concerns regarding the appearance of sunscreen should be addressed. If individuals do not feel comfortable with how a product looks or feels on the skin, they are much less likely to use it on a regular basis. There are many sunscreen formulations available; a sunscreen with an SPF of at least 30 is recommended. Additionally, sun protective clothing and sun avoidance are key components of photoprotection. 

Hydroquinone

In combination with photoprotection, hydroquinone is frequently selected as the first-line treatment for post-inflammatory hyperpigmentation.^[3] Hydroquinone works by blocking tyrosinase, thus preventing the conversion of dihydroxyphenylalanine to melanin. Additional mechanisms contributing to hydroquinone’s action in hyperpigmentation include inhibition of DNA and RNA synthesis, degradation of melanosomes, and melanocytotoxicity.^[3]  

While hydroquinone is highly effective as a monotherapy for post-inflammatory hyperpigmentation, it may be combined with other ingredients to improve results. For example, studies demonstrated benefit in combining hydroquinone with retinol.^[7,8] One open-label study showed a significant decrease in lesion size and pigmentation (evaluated clinically and via spectrophotometric analysis) as early as week 4 of treatment using hydroquinone 4%, retinol 0.15%, and antioxidants when compared to baseline.^[3,7] A similar study reported safety and efficacy of a regimen that included hydroquinone 4%, retinol 0.15%, and sunscreen, in a cohort in which the majority of patients had skin of color.^[3,8] 

While effective, hydroquinone use comes with some disadvantages. Long-term use, especially at high doses or when combined with other irritants (for example, retinoids), may lead to irritant reactions.^[3] Other adverse effects include allergic contact dermatitis, changes in nail color, contact leukoderma (patchy loss of skin color), the “halo effect” (hypopigmentation of skin surrounding the treated area), and exogenous ochronosis.^[3] Ochronosis is blue-black or blue-grey discoloration arising on skin treated with hydroquinone, usually on a chronic basis.^[3,9] Exogenous ochronosis is rare, reported mostly in Black individuals from South Africa.^[3] To avoid some of the severe complications associated with long-term use of hydroquinone, regimens should vary over time, alternating use of hydroquinone with a different depigmenting agent like mequinol, a retinoid, or azelaic acid.^[3,9] 

Mequinol

Mequinol is a derivative of hydroquinone that may be a reasonable substitute for hydroquinone in patients with sensitive skin as it is thought to be less irritating. It is often formulated with tretinoin to enhance penetration. Mequinol’s mechanism of action is unknown, but it may exert its effects via inhibition of tyrosinase, similar to hydroquinone.^[3] In one split-face study, similar results were noted with mequinol 2%/tretinoin 0.01% as compared to hydroquinone 4%.^[3,10] 

Retinoids

Retinoids are vitamin A analogues that can reduce post-inflammatory hyperpigmentation. Commonly used topical agents in this category include the first-generation retinoids, retinol and its metabolite, tretinoin, and third-generation retinoids, adapalene, and tazarotene (Table 1).^[3,11] Retinoids bind to retinol receptors and exert their effects via multiple mechanisms, including: inhibition of tyrosinase, increased keratinocyte turnover, and enhanced dispersion of keratinocyte pigment granules.^[3,11–13] Common adverse effects of topical retinoids include redness, irritation, and peeling.^[12,13] Retinoids are generally well-tolerated in patients with medium-dark skin tones. There is little evidence to suggest that individuals with skin of color are more susceptible to retinoid dermatitis than Caucasians.^[12] Since retinoid monotherapy for hyperpigmentation can yield slow results, retinoids are often combined with other ingredients such as hydroquinone.^[11,13] 

Adding Topical Steroids to Reduce Irritation  

The use of corticosteroids with agents prone to producing irritation, like hydroquinone and retinoids, can reduce the risk of inflammation, thus decreasing the risk of further hyperpigmentation.^[14] Several clinical trials have demonstrated the safety and efficacy of the use of combination formulas containing hydroquinone, tretinoin, fluocinolone acetonide in the treatment of melasma.^[15–18] Regimens containing corticosteroids are also used as adjunct therapy to treat post-inflammatory hyperpigmentation in clinical practice with success.

Azelaic Acid

Azelaic acid is a dicarboxylic acid that can be isolated from Pityrosporum ovale, which is the yeast responsible for pityriasis versicolor.^[3,5] Azelaic acid combats hyperpigmentation through multiple mechanisms: competitively inhibiting tyrosinase, suppressing melanocyte proliferation, and decreasing reactive oxygen species.^[3,5,13] Common adverse reactions include irritation, redness, and itching.^[13] 

In a 16-week study, 15% azelaic acid gel applied twice daily resulted in reduced acne and post-inflammatory hyperpigmentation in patients with Fitzpatrick skin types IV-VI when compared to baseline.^[5,19] 

Kojic Acid

Kojic acid is a fungal metabolite derived from certain species of Acetobacter, Aspergillus, and Penicillum.^[3,5] It works by chelating copper at the active site of tyrosinase, thus inhibiting tyrosinase.^[3,5,13] Kojic acid also acts as a scavenger of reactive oxygen species and has antioxidant properties.^[5,13] Contact dermatitis and sensitization are among the most common adverse effects.^[3,13] 

Studies regarding the efficacy of kojic acid compared to hydroquinone have yielded highly variable results.^[5] While kojic acid is only modestly effective as a monotherapy, it likely synergizes with other active ingredients like glycolic acid or hydroquinone.^[3,5] 

L-ascorbic Acid

L-ascorbic acid, or vitamin C, is a naturally-occurring antioxidant.^[3,5] In the context of skin-lightening, L-ascorbic acid works by inhibiting tyrosinase and thus, decreasing the synthesis of melanin.^[3,20] L-ascorbic acid is a relatively unstable compound, so it is often formulated with other depigmenting ingredients. Note that L-ascorbic acid also demonstrates antioxidant, photoprotective, and anti-inflammatory properties. Adverse reactions to L-ascorbic acid include yellowish discoloration of the skin, stinging, redness, and dryness.^[20] L-ascorbic acid is generally well-tolerated in skin of color.^[3] 

An in vitro study demonstrated that the vitamin C derivative, glyceryl‐octyl‐ascorbic acid, can effectively suppress melanogenesis by upregulating autophagy.^[21] Additionally, a split-face trial in Japan performed in ten patients with acne vulgaris demonstrated improvement in post-inflammatory hyperpigmentation using a lotion combining glyceryl‐octyl‐ascorbic acid, ascorbyl 2‐phosphate 6‐palmitate, and DL‐α‐tocopherol phosphate applied twice daily for 3 months.^[22] Several studies have also shown ascorbic acid to be an effective skin-lightening component in chemical peels.^[5] 

Niacinamide

Niacinamide, also known as nicotinamide, is the active form of niacin or vitamin B3.^[3,5] Unlike many other topical anti-hyperpigmentation agents, niacinamide does not act by inhibiting tyrosinase or decreasing cell proliferation.^[3] Niacinamide reduces hyperpigmentation by decreasing melanosome transfer to keratinocytes. Side effects of topical niacinamide are rare, but include mild burning, itching, and redness.^[23] 

One randomized, double-blind, vehicle-controlled study performed in forty-two Korean women, evaluated the efficacy of a formulation containing niacinamide and tranexamic acid.^[24] The study demonstrated a significant improvement in irregular facial pigmentation with the niacinamide and tranexamic acid treatment compared to the vehicle alone. While a study has demonstrated niacinamide to be effective in reducing axillary hyperpigmentation in women with skin of color, additional studies are needed to evaluate niacinamide’s effect on post-inflammatory hyperpigmentation in individuals with skin of color.^[3,5,25] 

Licorice Extracts

Glabridin is a licorice root extract commonly found in skin-lightening products.^[3,5] Glabridin inhibits tyrosinase, decreases UVB-induced pigmentation, and scavenges reactive oxygen species. It also possesses anti-inflammatory properties. Minimal adverse effects have been reported.^[3] In vitro studies have demonstrated that glabridin’s depigmenting effect was sixteen times that of hydroquinone.^[5,26,27] Additionally, a double-blind study that incorporated both in vivo and in vitro methods concluded that a hydroquinone-free compound containing glabridin and several other ingredients produced a significant decrease in hyperpigmentation compared to hydroquinone 4%.^[5,28] 

Liquiritin, a flavonoid component of licorice, can also be used as a depigmenting ingredient.^[3,5] It acts by enhancing dispersion of melanin and reducing inflammation. It can also reduce UVB-induced redness. Some studies suggested liquiritin improves discoloration in melasma, but further studies are needed to determine its efficacy in the treatment of post-inflammatory hyperpigmentation.^[5] 

Soy

Serine protease inhibitors derived from soy, like soybean trypsin inhibitor and Bowman-Birk inhibitor, decrease hyperpigmentation by inhibiting the protease-activated receptor 2 (PAR-2), a key mediator in melanosome transfer.^[3,29] By blocking the action of PAR-2, these soy proteins reduce melanosome transfer from melanocytes to keratinocytes, effectively decreasing pigmentation. Soy derivatives are often formulated with other depigmenting ingredients for a synergistic effect.^[3] 

In vitro and clinical trials demonstrated that soy is an effective depigmenting agent.^[3,5,29] In keratinocyte-melanocyte co-cultures, isolated soybean trypsin inhibitor and Bowman-Birk inhibitor reduced pigmentation.^[29,30] One double-blind, parallel-group randomized controlled trial evaluating a soy-containing moisturizer showed improvement in pigmentation and skin tone as well as other skin benefits versus vehicle alone in 65 female patients.^[5] Additionally, a 16-week study performed in patients with Fitzpatrick skin types III-V with acne-induced post-inflammatory hyperpigmentation showed efficacy of a formulation containing soy, salicylic acid, and retinol in reducing hyperpigmentation when compared to baseline and placebo.^[3] 

Table 3. Approach to reducing hyperpigmentation by ingredient. Many formulations combine two or more ingredients that may act synergistically to reduce hyperpigmentation.^{[3,5,11–13,20]}

Improvement in post-inflammatory hyperpigmentation can take several months to years if not treated, which can be highly discouraging, especially for those already struggling with the psychosocial burden of acne.^[1] Use of photoprotection and topical agents like hydroquinone, mequinol, retinoids, azelaic acid, kojic acid, ascorbic acid, niacinamide, and licorice extracts can accelerate the resolution of post-inflammatory hyperpigmentation.^[3]

Practical tips

• DO NOT forget to include sun protection as part of the first-line treatment of hyperpigmentation—it plays a key role in preventing further darkening of “dark marks” or “dark spots.”
• Many ingredients used in post-inflammatory hyperpigmentation can be irritating to the skin—this irritation can be minimized by starting with less concentrated formulations, slowly increasing frequency of use over time, or adding a topical steroid to the regimen.
• While hydroquinone is often thought of as a first-line agent in the treatment of hyperpigmentation, many other ingredients are effective in treating post-inflammatory hyperpigmentation with side effect profiles suitable for patients with skin of color.
• If hyperpigmentation is unresponsive to topical ingredients, other procedures such as chemical peels or laser therapy can be considered.