PIH Treatment | How To Get Rid Of Post Inflammatory Hyperpigmentation.

So your latest acne breakout has just cleared up but you’re left with noticeable marks all over your face. If those marks are brown, then it’s likely that you’ve got yourself some post-inflammatory hyperpigmentation. So what causes post-inflammatory hyperpigmentation? What are the treatment options for post-inflammatory hyperpigmentation? Is post-inflammatory hyperpigmentation permanent? Or does post-inflammatory hyperpigmentation go away?

What Causes PIH?

Post-Inflammatory Hyperpigmentation (PIH) occurs when inflammation or an injury to the skin causes an increase in the production of pigment. The most common cause of PIH is acne, but it can also occur as a result of physical injury to the skin, burns, allergic reactions, other inflammatory skin conditions, and therapeutic procedures (e.g. laser treatments and chemical peels) ^[1][2].

PIH predominantly affects darker skin types (Fitzpatrick III-VI) in the same location that the inflammation occurred. Lighter skin types (Fitzpatrick I & II) are more likely to experience Post Inflammatory Erythema (PIE), which presents as red marks ^[3]. However, it is not uncommon for people to experience both PIH and PIE.

Inflammation can cause melanocytes in the skin to either secrete more melanin or increase in number. In the case of acne, increased melanin is transferred to keratinocytes in the epidermis. Some other conditions can cause disruption to the basement membrane and allow melanin to fall into the dermis where it resides within macrophages ^[4].

Although the exact mechanism behind this reaction to inflammation is unknown, it is thought that the melanocytes are responding to the inflammatory mediators and reactive oxygen species (ROS) that are released during the inflammatory process ^[5]. This activates the melanocytes and increases the production of melanin and the transfer of pigment to the surrounding skin cells ^[3].

PIH Treatment

While post inflammatory hyperpigmentation can eventually resolve on its own, it can take months to years to fade when its limited to the epidermis and can be permanent if present in the deeper dermis ^[1].

However, there are a number of treatment options that can help improve the appearance of PIH.

The most important treatment for PIH is prevention and treatment of the underlying inflammatory skin condition (e.g. acne). For example, by avoiding picking, scratching, and rubbing at the skin and protecting the skin from UV radiation ^[3].

For epidermal hyperpigmentation, such as PIH after acne, there are a variety of topical lightening treatments available as well as chemical peeling and laser treatments. However, chemical peeling and laser treatment also carry the risk of further PIH occurring and topical treatments are unlikely to work for hyperpigmentation occurring in the dermis ^[6].

So what are the topical treatments for PIH and how do they work?

The majority of topical treatments for PIH exert their effects by inhibiting tyrosinase, a key enzyme in the production of melanin. This prevents the conversion of dihydroxyphenylalanine (DOPA) to melanin ^[1].

Hydroquinone

Hydroquinone therapy is often considered the gold standard for hyperpigmentation such as melasma and PIH. As well as inhibiting tyrosinase, some research suggests that hydroquinone may interfere with DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) synthesis, destroy melanocytes, and degrade melanosomes ^[7].

In the US, hydroquinone is available over the counter (OTC) at 2% concentrations and as a prescription at 3-10% concentrations, but it is most commonly used at strengths of 2-4% ^[2].

In a double-blind, placebo-controlled study of 48 melasma patients, a 4% hydroquinone cream was used daily by half the patients for 12 weeks (the other half used a placebo cream). At the end of the 12-week treatment period, 40% of those using hydroquinone experienced complete clearance of pigmented spots compared to 10% of those in the placebo group ^[8].

The 10% improvement seen in the placebo group may be explained by the fact that all participants were instructed to apply sunscreen daily in combination with their treatment creams (placebo or hydroquinone). In fact, it is well known that daily sunscreen use prevents hyperpigmentation from worsening and it is included in the treatment protocols for most hyperpigmentation disorders ^[9].

While hydroquinone is an effective treatment on its own with good to excellent results ^[10], the addition of antioxidants, retinoids, and alpha-hydroxy acids can improve its effectiveness and ability to penetrate the skin. For example, one study treated 17 PIH patients with a formulation containing 4% hydroquinone, 0.15% retinol, and antioxidants over a 12-week period. The majority of patients experienced 75% or more improvement in PIH, with some experiencing complete clearing. Significant decreases in pigmentation were seen as early as 4 weeks into the study ^[11].

The most extensively used hydroquinone combination therapy for PIH and melasma is known as the Kligman formula – a combination of 5% hydroquinone, 0.1% tretinoin, and 0.1% dexamethasone (a corticosteroid). This formula was able to completely clear hyperpigmentation in 5-7 weeks. However, none of these ingredients alone produced a substantial reduction in pigmentation within the 3-month treatment period ^[12].

More recently, the hydroquinone + retinoid + steroid formula has been adapted with different concentrations of ingredients and different steroids.

For example, one study looked at the combination of 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide (corticosteroid) 0.01%, as well as the combination of the hydroquinone and retinoid, retinoid and steroid, and hydroquinone and steroid, in 641 patients over an eight-week period.

The ‘triple-combination’ formula resulted in 26.1% of patients experiencing a complete clearing of hyperpigmentation compared to 4.6% of those in the other treatment groups. In addition, at the end of the 8-week treatment period, 70% of patients in the ‘triple-combination’ group saw a reduction in their pigmentation of at least 75%. This was in comparison to 30% of patients in the other ‘dual-combination’ groups experiencing improvements of at least 75% ^[13].

It is important to note that a number of the authors of this study work for the manufacture of the ‘triple-combination’ formulation used (Tri-Luma, Galderma) which may represent an element of bias.

Nevertheless, the combination of hydroquinone with a retinoid and steroid is widely considered the ‘gold-standard’ of treatment for hyperpigmentation.

That brings us on to our next topical treatment for PIH – retinoids.

Retinoids

Retinoids are derivatives of vitamin A that work by increasing epidermal turnover. In the case of hyperpigmentation, this increase in cell turnover facilitates the distribution and removal of melanin ^[1].

As already mentioned, the ‘gold standard’ of hyperpigmentation treatment includes the use of retinoids alongside hydroquinone and steroids. However, retinoids can also be effective when used on their own.

For example, one study compared 0.1% tretinoin with a placebo over a 40-week period on 54 subjects with PIH. All subjects were supplied with SPF15 sunscreen to be applied daily and were instructed to avoid excessive exposure to sunlight, wind, and cold.

The group that applied the 0.1% tretinoin experienced significant overall improvement, with 58% of subjects demonstrating lightened lesions (compared to 7% in the placebo group) that occurred as early as 4 weeks after the treatment began and continued to lighten as the study progressed.

Histological analysis revealed that the epidermal melanin content decreased by 23% in the tretinoin group compared to 3% in the placebo group. This study concluded that 0.1% tretinoin can speed up the resolution of PIH and, once cleared, this PIH did not return once treatment was stopped ^[14].

Synthetic retinoids, such as adapalene and tazarotene, have also demonstrated effectiveness as treatments for PIH. For example, 0.1% adapalene gel improved PIH after 12 weeks of use in a study of 65 acne patients ^[15]. Similar effectiveness was seen with the daily use of a 0.1% tazarotene cream over an 18-week period in a study of 74 patients with PIH ^[16].

One issue with retinoids is the skin irritation that often accompanies their use. As this irritation often manifests as inflammation, it is important to build up a tolerance in order to prevent further PIH.

All-trans-retinol is a precursor of retinoic acid that is available over the counter and tends to be less irritating. Retinol offers similar skin benefits to retinoic acid but at a smaller magnitude ^[17]. Basically, retinol is less irritating and less likely to cause irritation, but it’s going to take longer to see the effects.

Azelaic Acid

Azelaic acid is a dicarboxylic acid that is naturally produced by Pityrosporum ovale (a yeast that lives on normal skin) and is often used to treat acne vulgaris as well as acne rosacea ^[1]. As azelaic acid inhibits tyrosinase, as well as inhibiting DNA synthesis of abnormal melanocytes, it can also be an effective treatment for PIH ^[18].

Interestingly, this selectivity of azelaic acid towards abnormal melanocytes means that it has no de-pigmenting effect on normally pigmented skin and freckles ^[18].

In one randomized, double-blind study, A cream containing 20% azelaic acid was compared to the same cream without azelaic acid (vehicle) over a 24-week period. The patients that used the azelaic acid cream experienced significant improvements compared to those who used the vehicle and reported higher levels of satisfaction with the treatment ^[19].

When 20% azelaic acid cream was combined with a lotion containing 15-20% glycolic acid it demonstrated the same effectiveness as 4% hydroquinone in the improvement of hyperpigmentation ^[20].

In other studies, 20% azelaic acid was as effective as ^[21]or better than ^[22]2% hydroquinone at reducing hyperpigmentation.

These studies all evaluated azelaic acid at prescription strength, but it is available over the counter at lower concentrations that will offer similar results with less irritation. However, these results may take longer to achieve.

Niacinamide

Niacinamide (also known as nicotinamide) is a water-soluble form of vitamin B3 that has a wide range of benefits for skin, including improving skin hydration, acne, rosacea, and PIE. In addition, niacinamide has demonstrated anti-pigmentation effects.

In vitro studies have demonstrated that niacinamide can decrease the transfer of melanosomes from melanocytes to keratinocytes by up to 68% ^[23]. Which basically means that it stops pigment leaking into skin cells. Research also suggests that niacinamide interferes with the cell signaling pathways between keratinocytes and melanocytes ^[23].

In human (in vivo) studies, niacinamide has demonstrated effectiveness at preventing pigmentation and reducing existing pigmentation. For example, one study found that 5% niacinamide prevented seasonal-induced increases in pigmentation when used twice daily for 12 weeks ^[24]. In other words, it prevented pigmentation from UV radiation during the months when it is particularly strong.

Another study found that 4% niacinamide significantly decreased hyperpigmentation, while 2% niacinamide increased skin lightening, in as little as 4 weeks ^[23].

When compared to 4% hydroquinone, 4% niacinamide provided equally as good results in colorimetric measures. However, a higher percentage of patients using hydroquinone reported good to excellent improvement (55% vs 44%) but with more experiencing side-effects (29% vs 18%) ^[25].

Niacinamide is available both as a prescription and in cosmetics at varying strengths.

Vitamin C

Vitamin C, also known as ascorbic acid, is the most abundant antioxidant in the skin and co-exists with other antioxidants to protect the skin from free radicals, such as reactive oxygen species (ROS). It is essential for collagen production and can help prevent premature aging and skin cancers due to sun overexposure.

Research has demonstrated that vitamin C can also inhibit tyrosinase, thereby decreasing melanin production and reducing PIH ^[26]. In fact, one study identified that 5% ascorbic acid was as effective as topical therapy with 4% hydroquinone at reducing hyperpigmentation ^[27].

As vitamin C is unstable and rapidly oxidized, it is often combined with other hyperpigmentation-reducing ingredients, such as licorice extracts and soy, to enhance its effectiveness ^[28].

There are a number of different active forms of vitamin C, but L-ascorbic acid appears to be the most biologically active and well-studied. In order to provide stability and permeability, L-ascorbic acid should have a pH of less than 3.5 and works best at concentrations of 8-20% ^[29].

Other Topical Treatments For PIH

• N-Acetyl Glucosamine (NAG) is an amino-monosaccharide that inhibits tyrosinase glycosylation and thus melanin production. 2% NAG can reduce the appearance of hyperpigmentation within 8-weeks of use, and these reductions are greater when 2% NAG is combined with 4% niacinamide ^[30].
• Mequinol is a derivative of hydroquinone that may inhibit tyrosinase and melanin production ^[1]. When combined with 0.01% tretinoin, 2% mequinol is as effective as 4% hydroquinone at reducing PIH ^[31].
• Kojic Acid is a potent tyrosinase inhibitor that is effective at reducing pigmentation when combined with glycolic acid and/or hydroquinone ^[32].
• Arbutin is a naturally occurring derivative of hydroquinone that is extracted from the dried leaves of various fruit plants. It acts as a tyrosinase inhibitor and prevents the maturation of melanosomes ^[1]. Synthetic forms of arbutin (alpha-arbutin and deoxyarbutin) are better at inhibiting tyrosinase than the original arbutin and 3% deoxyarbutin demonstrated effectiveness at lightening pigmentation in light-skinned patients ^[33].
• Licorice Extract contains several active agents that inhibit tyrosinase, including glabridin and licochalone, as well as liquiritin which reduces pigmentation by dispersing melanin ^[1].
• Soy proteins can reduce pigmentation by inhibiting the transfer of melanosomes from melanocytes to keratinocytes. Soy has demonstrated effectiveness at reducing PIH when combined with an SPF 15 moisturizer and when formulated with salicylic acid and retinol ^[1].
• Resveratrol is a natural polyphenol that is found in various fruits and vegetables (particularly red grapes and therefore red wine). It can inhibit melanin synthesis in a number of ways, both directly and indirectly. For example, resveratrol directly inhibits tyrosinase by acting as an alternative substance for tyrosinase. Indirectly, resveratrol can inhibit the transcription of tyrosinase and regulate it after transcription ^[34].
• Zinc possesses antioxidant and sun protection properties and can act as an anti-inflammatory. It is thought that these properties are the main reason that zinc can reduce PIH, however, it is also possible that zinc plays a role in tyrosinase metabolism ^[35].

Chemical Peels and Hydroxy Acids (AHA/BHA)

Hydroxy acids, such as glycolic acid, lactic acid, and salicylic acid act as chemical exfoliants that can help remove dead skin cells and loosen the top layer of skin. Hydroxy acids generally fall into three main categories; alpha-hydroxy acids (AHAs; e.g. glycolic acid, lactic acid), beta-hydroxy acids (BHA; e.g. salicylic acid), and poly-hydroxy acids (PHA; e.g. lactobionic acid) ^[36].

Hydroxy acids can speed-up the resolution of PIH and other pigmentary disorders by increasing skin cell turnover ^[37]. This means that skin pigment is brought to the surface of the skin faster where it is shed as part of normal epidermal desquamation. This process would usually take approximately 4 weeks ^[38]. Some in vitro research also suggests that glycolic acid and lactic acid inhibit tyrosinase and can suppress melanin formation in human and mouse melanoma cells ^[39].

In one study, 8% lactic acid improved the hyperpigmentation associated with photodamage after 22 weeks of twice-daily application ^[40]. In terms of PIH, a gel containing 2% hydroquinone, and 10% glycolic acid was applied twice daily with a 0.05% tretinoin cream applied at night. In addition, half of the patients received a series of six glycolic acid peels. All patients showed a significant improvement in their PIH, however, those who received the additional glycolic acid peels had a greater improvement in a shorter amount of time, although the difference between groups was not statistically significant ^[41].

Other research has found that both 35% glycolic acid peels and combination 20% salicylic acid/10% mandelic acid peel equally reduce pigmentation effectively ^[42].

More recently, a hybrid of glycolic acid and resveratrol, resveratryl triglycolate, has demonstrated the ability to reduce sun-induced pigmentation when applied twice daily for 6-8 weeks ^[43]. Glycolic acid can also be combined with kojic acid and/or hydroquinone to effectively reduce pigmentation ^[44][45].

PIH Treatment Summary

So What Causes Post Inflammatory Hyperpigmentation?

PIH occurs as a result of injury to the skin or inflammation causing an increase in the production of pigment. Although it is not fully known why this reaction occurs, it appears that inflammatory mediators and ROS released during the inflammatory process activates melanocytes and increases the production of melanin and the transfer of pigment to surrounding skin cells.

How To Get Rid Of Post Inflammatory Hyperpigmentation – Treatment Options

The first step toward getting rid of PIH involves treating the underlying inflammation (e.g. acne) to prevent further PIH from occurring. In addition, other preventative measures such as sun protection should be adopted.

The gold standard for the treatment of hyperpigmentation (including PIH) involves a combination of retinoids, hydroquinone, and steroids. However, there are a number of over the counter options that are available. These include:

• Retinol
• Azelaic Acid
• Niacinamide
• Vitamin C
• Kojic Acid
• Alpha-Arbutin
• Liquorice Extract
• Soy Proteins
• Resveratrol
• Zinc
• Hydroxy Acids (AHAs/BHAs)

Often, a combination of these topical ingredients is required to increase the effectiveness of any one ingredient (e.g. niacinamide + zinc and glycolic acid + resveratrol).

Is Post-Inflammatory Hyperpigmentation Permanent Or Does Post Inflammatory Hyperpigmentation Go Away?

PIH is likely to fade on its own as long as broad-spectrum sunscreens are used and the underlying inflammatory condition/ injury is controlled. However, the resolution of PIH can be enhanced by the various mentioned treatments, particularly when multiple treatments are combined.

For example, combining ingredients that have different mechanisms of action as seen here: 

As you can see, the ‘gold standard’ treatment for PIH includes ingredients that have their effects at different points in the melanin production process (retinoids before, hydroquinone during, and corticosteroids after melanin production). For this reason, it may be more effective to combine three ingredients that cover the before, during, and after the melanin production process. For example, retinol + niacinamide + zinc, or retinol + azelaic acid + vitamin C.

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