42 Practical Dermatology February 2005

When hyperpigmentation brings patients to your office, be prepared to offer effective, efficient interventions.

By Rebat M. Halder, MDWashington, DC

Dyschromia accounts for a significant number of dermatologyvisits by patients of color. Postinflammatory hyperpigmenta-tion and melasma are among the most common presenta-tions for which patients with darker skin seek dermatologiccare; pigmentary disorders account for the third most com-

mon dermatologic diagnosis in blacks, Hispanics, and Asians.1

Despite the relatively high incidence of hyperpigmentation disor-ders, treatment remains notoriously challenging. Effective optionsexist, but these may be associated with irritation, slow onset, andparadoxically in some cases risk of inflammation and subsequentpigmentary alteration. Dermatologists must work closely withpatients to develop effective regimens, promote compliance, andencourage healthy patient behaviors, such as sun avoidance.

Understanding CausesPostinflammatory hyperpigmentation frequently develops as aresult of inflammatory cutaneous disorders or irritation associatedwith topical therapeutic interventions. Both topical retinoids andbenzoyl peroxide may be associated with cutaneous irritation andsubsequent development of hyperpigmentation. Interestingly, top-ical retinoids are also a potential treatment for hyperpigmentation.

Postinflammatory hyperpigmentation is a normal biologicalresponse in human skin. It may develop as a response to papu-losquamous diseases (such as allergic contact dermatitis, lichenplanus, etc.), vesiculo-bullous diseases (such as bullous pem-phigoid, herpes zoster, etc.), or inflammatory diseases, primarilyacne. Post-inflammatory hyperpigmentation is a common seque-lae of acne vulgaris, particularly in patients of color. Many patientsreport greater distress over subsequent hyperpigmented maculesthan over acne lesions themselves.2

Melanin production may remain unchanged in response tocutaneous trauma or inflammation, but in some cases, melanocytescan react with increased production. The actual pathogenesis ofpostinflammatory hyperpigmentation is unknown, although theactions of cytokines and inflammatory mediators from ker-atinocytes on melanocyte function are implicated.

Recent research suggests that heat could play a role in develop-ment of melasma.3 Ambient heat and subsequent increased cuta-neous temperature may influence melanocyte function; furtherstudy is indicated. Meanwhile, dermatologists should counselpatients about the risk and urge avoidance of excessive heat (includ-ing standing over hot stoves, in front of fireplaces, etc.).

Diagnostic TipsPostinflammatory hyperpigmentation develops due to an increasein melanin production, an abnormal distribution of melanin pig-

ment, or both.4 Epidermal melanin appears brown in color, where-as dermal melanin tends to have a blue or bluish-gray appearance.5

Use of a Wood’s lamp may help distinguish between dermal andepidermal melanin deposition. The lamp shone on the skin willenhance the epidermal component while the dermal componentwill become unapparent. However, due to optical factors, theWood’s lamp does not always prove useful in persons of color.Hyperpigmentation disorders in which the melanin is epidermalare easier to treat than those in which melanin is dermal.5 It is crit-ical that physicians attempt to uncover underlying causes ofhyperpigmentation and attempt to treat them. Eliminating con-tributory disease processes is the only way to prevent further devel-opment of dyschromia.

Skin Care and Sun Avoidance BasicsSun avoidance and sun protection are critical elements of therapyfor patients with hyperpigmentation. Use of a broad-spectrum sun-screen in conjunction with one of the phenolic or nonphenolictherapies discussed below is first-line therapy for hyperpigmenta-tion. Failure to adhere to appropriate sun protection strategies cancontribute to redevelopment of hyperpigmentation and reverse thetherapeutic benefits of topical therapy. Given the potentiallylengthy duration of ther-apy to diminish hyper-pigmentation, neitherpatients nor physicianswelcome the prospect ofredevelopment ofdyschromia.

Counsel patients toselect a broad-spectrum(UVA/UVB) sunscreenproduct for daily use.Physical sunscreens pro-vide more protectionthan chemical sun-screens, however, theyare not as cosmeticallyelegant. They can leavean ashy residue that ismore pronounced indarker skin. There arenumerous sunscreen formulations available at various concentra-tions, formulations, and costs, providing patients ample opportu-nity to identify a product that fits their individual preferences,thus promoting compliance. Given the nature of potential con-

February 2005 Practical Dermatology 43

Phenolic hydroquinone

has been the

gold-standard of

hyperpigmentation

therapy for over

half a century.

44 Practical Dermatology February 2005

tributory diseases (allergic contact dermatitis, acne) and thepotential contributory role of irritation and inflammation in thedevelopment of hyperpigmentation, patients should avoidpotentially irritating skincare products or practices. Encouragepatients to adopt simplified skin care regimens using non-come-dogenic/non-acnegenic, non-sensitizing cleansing and moistur-izing products. Avoid scrubbing or other mechanical manipula-tion. Color cosmetics, when used, should also be non-comedo-genic/non-acnegenic. Some patients with mild pigmentaryalteration may find that use of camouflaging color cosmeticsobviates the need for topical drug therapy.

Therapeutic OptionsA number of agents currently available (described below) and indevelopment (see sidebar) provide improvement in cases ofdyschromia, though efficacy is variable. Achieving maximalresponse often depends on the skill of the physician to select theappropriate agent or combination of agents as well as appropri-ate adjunctive interventions on a patient-by-patient basis.

Hydroquinone. Phenolic hydroquinone has been the gold-standard of hyperpigmentation therapy for over half a century.It is available over-the-counter in 2% formulations and by pre-scription in 3-4% concentrations (Claripel, Stiefel;EpiQuinMicro, SkinMedica; Glyquin, Valeant; Lustra, Medicis;TriLuma, Galderma). Higher concentrations, from 5-10%, maybe compounded. These higher strengths may be irritating andunstable, but they may be necessary to treat extremely darkpostinflammatory hyperpigmentation or melasma. Gradualtitration of hydroquinone to higher concentrations and/orincorporation of a topical corticosteroid can limit adverse reac-tions and improve tolerability of therapy for patients.

Hydroquinone exerts its effect by inhibiting the enzymetyrosinase, reducing the conversion of dihydroxyphenylalanine(DOPA) to melanin. Additional proposed but unproven mech-anisms include destruction of melanocytes, degradation ofmelanosomes, and inhibition of DNA and RNA synthesis.6

Though lower OTC concentrations demonstrate efficacy, theonset of action is generally significantly delayed compared tothat of hydroquinone 3% or higher.

Co-administration of vitamin C, retinoids, or alpha-hydroxyacids topically can enhance the efficacy of hydroquinone byincreasing penetration of the agent. Certain formulations ofhydroquinone, such as Lustra and Glyquin, incorporate AHAsand antioxidants into the formulation. Exercise caution, asretinoids and AHAs may also be associated with development ofcutaneous irritation.

Adverse reactions to hydroquinone include irritant and aller-gic contact dermatitis, which may result in postinflammatoryhyperpigmentation, and nail discoloration. Hypopigmentation ofnormal skin surrounding treatment areas may also develop. These

side effects usually resolve with discontinuation of therapy.2

Exogenous ochronosis may result from exposure to hydro-quinone, but only 45 cases have been reported in NorthAmerica despite a significant history of use of the agent.However, in South Africa, where women often use very highconcentrations of hydroquinone over large surface areas, reportsare more common.7

Arbutin. A plant-derived compound, arbutin is the B-D-glucopyranoside derivative of hydroquinone, effective in man-aging hyperpigmentation characterized by hyperactive mel-anocytes.8,9 The agent is available in a range of non-prescriptionproducts in a 3% concentration. Studies demonstrate a dose-dependent reduction in tyrosinase activity and melanin contentin melanocytes. Higher concentrations demonstrate greater effi-cacy than lower concentrations, but the former may paradoxi-cally produce hyperpigmentation. Arbutin and kojic acid (dis-cussed below) are indicated in those patients who develop aller-gic reactions to hydroquinone or those who have been usinghydroquinones for an extended period of time to help diminishthe risk of developing exogenous ochronosis.

Kojic Acid. A naturally-occurring hydrophilic fungal deriva-tive used in the treatment of hyperpigmentation disorders, kojicacid is also available in a range of over-the-counter skin careproducts in concentrations from 1-4%. It inhibits tyrosinasewith efficacy similar to hydroquinone.

Initial excitement for kojic acid focused heavily on the lackof any sensitizing activity associated with the agent. In fact, kojicacid is widely used in skin care products in Japan. However,recent long-term data from Japan show that kojic acid may pro-duce contact dermatitis and erythema.10

Azelaic Acid. This naturally occurring, non-phenolic agentoriginally developed for treatment of acne inhibits tyrosinase andsubsequently improves hyperpigmentation. Azelaic acid 20%(Azelex, Allergan) is approved in the US for treatment of acnebut is widely used off-label for post-inflammatory hyperpigmen-tation.11 Many clinicians include azelaic acid as an element of thefirst-line topical treatment regimen for acne in patients of coloror those with a history of post-inflammatory hyperpigmentation.Azelaic acid reduces production of free radicals, which studiesimplicate in development of post-inflammatory hyperpigmenta-tion.12 Additionally, by inhibiting DNA synthesis and mitochon-drial enzymes, it is cytotoxic to melanocytes.13

Whereas one study found azelaic acid 20% equivalent to 2%hydroquinone in management of melasma,14 another showed the20% concentration is better.15 It has also been used in manage-ment of lentigo maligna and other hyperpigmentation disor-ders.2,4 Azelaic acid will not depigment normally pigmented skin,freckles, senile lentigines, and nevi. This may reflect the fact thatthe agent selectively acts on abnormal melanocytes.

Topical Retinoids. The mechanism of action of topical

Hyperpigmentation

February 2005 Practical Dermatology 45

tretinoin (Retin-A, Ortho-Neutrogena; Avita, Bertek) in hyper-pigmenation is poorly understood, but possible inhibition oftyrosinase and subsequent reduction in epidermal melanin aresuspected.16 Topical tretinoin 0.05-0.1% as monotherapydemonstrates efficacy in the management of postinflammatoryhyperpigmentation and melasma; however, longer treatmentperiods, lasting 20-40 weeks, may be necessary.

After 40 weeks of therapy, black subjects treated withtretinoin in one study had significantly lighter post-inflamma-tory lesions compared to controls. Epidermal melanin contentof lesions had decreased 23 percent in the treated group com-pared to three percent in controls.17

Forty weeks of tretinoin monotherapy yielded a 32 percentimprovement in the Melasma Area and Severity Index score inblack patients compared to 10 percent improvement in the con-trol group. Sixty-seven percent of treated patients experiencedmoderate side effects of desquamation and erythema.18,19 Darkerskinned patients who develop a dermatitis from tretinoin thera-py risk developing hyperpigmentation as a response to the der-matitis. This is often called retinoid hyperpigmentation.20

The retinoid analogue, adapalene (Differin, Galderma), is analternative to tretinoin. In one study comparing adapalene 0.1%to tretinoin 0.05% cream in management of melasma, adapa-lene demonstrated similar efficacy with fewer side effects andgreater patient acceptability. Because retinoids are effective forpostinflammatory hyperpigmentation, they are a good medica-tion to use to simultaneously treat both acne and post-inflam-matory hyperpigmentation from acne.

Topical Corticosteroids. Hypopigmentation is a well-docu-mented side effect of long-term topical corticosteroid use.However, reliably influencing pigmentation with topical corti-costeroids may be somewhat difficult. Nonetheless, topical cor-ticosteroids have been used alone or in combination with othertopical agents to improve hyperpigmentation. These agentsdemonstrate variable effect when used as monotherapy to treatpost-inflammatory hyperpigmentation or when used asmonotherapy or combination therapy for melasma.

Combination TherapyCombination regimens designed to balance the relativestrengths and weaknesses of the various available agents mayyield optimal results by allowing for more rapid clearance andenhancing outcomes. The first published study of combinationtherapy used tretinoin 0.1%, hydroquinone 5%, and dexam-ethasone 0.1% for postinflammatory hyperpigmentation.21

Tretinoin reduced the atrophy of the corticosteroid andenhanced penetration of the hydroquinone, while the corticos-teroid helped diminish tretinoin-induced irritation. Now, a sim-ilar FDA-approved combination formulation is available in theUS (Tri-Luma). It incorporates fluocinolone acetonide, hydro-

quinone 4%, and tretinoin 0.05%. In studies, 78 percent ofpatients treated with the formulation for melasma demonstrat-ed near or complete clearing after eight weeks of therapy. A 12-month study demonstrated similar efficacy and safety.22

Some dermatologists compound similar tretinoin/corticos-teroid/hydroquinone formulations with higher concentrations ofhydroquinone. Alternatively, if compounding is unavailable,physicians may develop therapeutic regimens that include use ofa topical hydroquinone cream plus a layering application of aseparate topical retinoid or topical corticosteroid on top of thefirst cream.

Linea Nigra: A Unique Presentation

The linea alba is a pale line that normally appears toextend from the xyphoid process over the abdomenthrough the umbilicus to the symphysis pubis. Duringpregnancy, when the line darkens, it is called the lineanigra.23,24 Similar darkening may appear around the nip-ples, areola, perineum, vulva, and inner thighs.25 Thoughthe exact mechanism of this benign and common condi-tion is unclear, hormonal mechanisms are likely at play.

Up to 90 percent of pregnant women may developlinea nigra; pigmentation is usually more intense inwomen of color. This gestational pigment darkening usu-ally resolves naturally within several months post-par-tum.26

Agents in Development• NCAP (N-acetyl-4-cysteaminylphenol). This phenolicagent currently in development but not yet available inthe US demonstrates efficacy in the management ofmelasma. In a retrospective study of 12 melasmapatients treated with NCAP, 66 percent showed markedimprovement and eight percent had complete clearance.The agent began to demonstrate efficacy within two tofour weeks.27,28

• Licorice extract. With a mechanism of action similar tothat of kojic acid, licorice extract is used across theworld. Its primary component, glabridin, demonstratesthe ability to inhibit tyrosinase activity, blocking melano-genesis and inflammation. But the agent does notappear to affect DNA synthesis.1

1. Halder RM, Nootheti PK. Ethnic skin disorders overview. J Am Acad Dermatol 2003; 48(Suppl.):S143-48.2. Grimes PE, Stockton T. Pigmentary disorders in blacks. Derm Clinics 1988;6:271-281.3. Willis I. Cutaneous Heat: A potential environmental factor in the development of melasma. CosmeticDermatology 2004;17(6):387.

4. Tomita Y, Maeda K, Tagami H. Melanocyte-stimulating properties of arachidonic acid metabolites: possi-ble role in postinflammatory pigmentation. Pigment Cell Res 1992 Nov;5(5 Pt 2):357-361.5. Gilchrest BA. Localization of melanin pigmentation in skin with Wood lamp. British Journal Dermatology.1977;96:245-247.6. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol. 1995;181:1453-57.7. Levin CY, Maibach H. Exogenous ochronosis: An update on clinical features, causative agents, and treat-ment options. Am J Clin Dermatol 2001:2;213-17.8. Maeda K, Fukuda M. Arbutin: Mechanisms of its depigmenting action in human melanocyte culture. JPharm Exp Ther 1996; 276:765-9.9. Lei TC, Virador VM, Vleira WD, et al. A melanocyte-keratinocyte coculture model to assess regulators ofpigmentation in vitro. Anal Biochem 2002;305:260-8.10. Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermatitis1998;89:86-7.11. Breathnach AS. Melanin hyperpigmentation of ski: melasma, topical treatment with azelaic acid, andother therapies. Cutis 1996;57:36-45.12. Lowe NJ, Rizk D, Grimes, PE, et al. Azelaic acid 20% cream in the treatment of facial hyperpigmenta-tion in darker-skinned patients. Clin Ther 1998;20:945-59.13. Nguyen QH, Bui TP. Azelaic acid. Pharmacokinetic and pharmacodynamic properties and its therapeuticrole in hyperpigmentary disorders and acne. Int J Dermatol 1995;34:75-84.14. Balina LM, Graupe K. The treatment of melasma: 20% azelaic acid versus 4% hydroquinone cream. IntJ Dermatol 1991;80:893-95.15. Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone

in the treatment of melasma. Acta Derm Venereol. 1989;143(Suppl):58-61.16. Dogra S, Kanwar AJ, Parsad D. Adapelene in the treatment of melasma: A preliminary report. J Dermatol2002;29:539-40.17. Bulengo-Ransby Sm, Griffiths CE, Kimbrough-Green CK, et al. Topical retinoic acid (retinoid acid ) ther-apy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med1993;328:1438-44. 18. Kimbaugh-Green CK, Griffiths CE, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in balckpatients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130:727-33.19. Griffiths CE, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. A vehicle-con-trolled clinical trial. Br J Dermatol 1993;129:415-421.20. Perez A, Sanchez JL. Treatment of acne vulgaris in skin of color. Cosmetic Derm 2003;16(Suppl):23-28.21. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 1975;111:40-8.22. Galderma Laboratories. Data on file. Fort Worth, TX; Galderma Laboratories 2003.23. Winton GB, Lewis CV. Dermatoses of pregnancy. J AM Acad Dermatol 1982;6:997-998.24. Beischer Na, Wein P. Linea alba pigmentation and umbilical deviation in nulliparous pregnancy: the lig-amentous sign. Obstet Gynecol. 1996 Feb;87(2):254-256.25. Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol 2001;45:1-19.26. Lawley TJ, Yancey K. Skin chances and diseases of pregnancy. In: Dermatology in General Medicine,5th ed. Freedberg IM, et al. eds. New York, McGraw-Hill 1999; p 1963.27. Alena F, Dixon W, et al. Gutathione plays a key role on the depigmenting and melanocytic action of N-acetyl-2-S-cysteaminylphenol in black and yellow hair follicles. J Invest Dermatol 1995;104:792-7.28. Jimbow K. N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanodermaof patients with melasma. Arch Dermatol 1991;127:1528-34.29. Yokota T, Nishio H, Kubota Y, et al. The inhibitory effect of labridin from licorice extracts on melano-genesis and inflammation. Pigment Cell Res 1998;11:355-61.

46 Practical Dermatology February 2005

Beware of Medication AbuseContrary to FDA regulation, some prescription-strength corti-costeroid and hydroquinone products may be available topatients over-the-counter. This is particularly true in largerurban centers, such as Washington, DC, New York City, LosAngeles, and Miami, where ethnic stores often carry these“skin care” products. Available corticosteroids may be high-potency (class 1 and 2), while hydroquinone products aregenerally available in a range of strengths.

While cases of exogenous ochronosis have remained lowdespite a very high rate of use of hydroquinone in the US, therate of adverse events may increase significantly as greaternumbers of patients obtain and use high-strength hydro-quinone without physician supervision.

Consider Adjuvant MeasuresUse of microdermabrasion in conjunction with topical thera-py is common in management of hyperpigmentation.Chemical peels may also prove beneficial as additive measuresin hyperpigmentation treatment. Superficial chemical peels,such as beta-hydroxy acids (salicylic acid), are very effective intreating post-inflammatory hyperpigmentation from acneand may improve acne itself.

In melasma, chemical peels are useful as part of a mainte-nance regimen in combination with daily use of bleachingagents. However, chemical peels must be done on a regularbasis to provide notable benefit in melasma. Micro-

dermabrasion is effective for postinflammatory hyperpigmenta-tion from acne but is not very helpful for melasma. Lasers havenot demonstratedsignificant efficacyin management ofmelasma, but theymay be effective fornevus of Ota orpostinflammatoryhyperpigmentation.The 694nm Q-switched ruby laser,in particular, hasdemonstrated bene-fit.

However, all ofthese modalitieshave potential sideeffects, includingpigmentary alter-ation, when used inskin of color.Therefore, usethem judiciouslyand only when youare comfortabledoing so.

Hyperpigmentation

Combination regimens

designed to balance

the relative

strengths and

weaknesses of the

various available

agents may yield

optimal results