Lynde Institute for Dermatology, Markham, ON, Canada

Introduction

Patients often seek natural approaches to treating skin disease. Colloidal oatmeal has been used for decades to improve atopic dermatitis and soothe other pruritic and xerotic dermatologic conditions.¹ Although initially developed because of historical use, data is growing supporting its myriad benefits.

Background

• Oats have long been used as treatment for skin disorders and to beautify the skin.
  • The oldest oat grains were found in Egypt around 2000 BC^2,3 and the nutritional value of oatmeal and its topical benefits have been recognized since Roman times.^2-4
  • Oats were introduced into North America in the 17^th century.²
• In 1945 a ready to use colloidal oatmeal for skin care became available.³
  • Colloidal oatmeal is produced by grinding fine granules of oatmeal and subsequently boiling it to extract the colloidal material.
  • A colloid is a substance microscopically dispersed evenly throughout another substance.
• Colloidal oatmeal was approved by the Food and Drug Administration (FDA) as a skin protectant agent for over-the-counter use in 2003.⁵
  • One approved listings is that it “temporarily protects and helps relieve minor skin irritation and itching”.⁵
• It is recognized as a natural health product skin protectant ingredient by Health Canada.⁶
• Atopic dermatitis (AD) is a common, chronic, pruritic skin condition with a high prevalence in children.
  • Although AD has a complex pathogenesis there is substantial evidence that a genetically impaired skin barrier plays a role in its development.^1,7,8
  • The defective barrier allows irritants and antigens to penetrate leading to inflammation.⁹
  • Decreased stratum corneum hydration also leads to skin inflammation.¹⁰
  • This leads to the itchy eczematous lesions of AD.
  • Thus, restoration of skin barrier and stratum corneum hydration, soothing of itch and reduction of inflammation are critical for improvement of AD and quality of life for the patient and their families.¹
  • Moisturization and barrier protection play a central role in the treatment of AD.
  • They are recommended as first line and adjunctive agents for the management of AD.^11,12

Oatmeal Properties

• Colloidal oatmeal has multiple properties that make it ideal for managing AD and other xerotic and pruritic skin conditions.
• The small particles of the oat proteins form an occlusive barrier, protecting the skin from external agents^1,13 and preventing moisture loss.
• It contains high concentrations of starches and beta-glucan that create an occlusive film and exhibit water-absorbing properties.¹⁴ It also has antioxidant (e.g. avenanthramides, vitamin E, ferulic acid, caffeic acid)^3,4,15 and anti-inflammatory properties.^16,17
• Aventhramides are phenolic compounds with potent anti-inflammatory activity, through inhibition of NF-KB in keratinocytes and inhibition of the release of the pro-inflammatory cytokine IL-8.¹⁸
  • The level of anti-inflammatory effect is similar to that of topical 1% hydrocortisone.¹⁸
  • Colloidal oatmeal can also act as a skin buffer, restoring the pH of the skin to normal.⁴

Efficacy

• The benefits of colloidal oatmeal have been known for decades and several studies as early as the 1950s have reported the hydrating, soothing, protective and anti-irritant properties in AD.^1,19-21
• In the study by Nebus et al.,²² twenty-five patients aged 12 to 60 years were enrolled in the 8-week study.
  • Inclusion criteria included mild to moderate AD with at least 5% body surface area (BSA).
  • They used a topical regimen of twice-daily oat-based occlusive cream and a once-daily oat-based body wash.
  • Patients were permitted to continue their topical prescription AD treatments, however, patients on systemic medications for their AD were excluded.

• The results demonstrated that daily use of the adjunctive oat-based regimen significantly improved AD outcomes at all time points compared to baseline: Investigators Global Assessment (IGA), Eczema Area and Severity Index (EASI), and itching. Dermatology Life Quality Index (DLQI) was significantly improved from baseline at weeks 4 and 8.
• Some patients became clear of eczema as early as week 2 of use and over 45% of patients were clear or almost clear by week 8.
• Safety assessments revealed the regimen was well tolerated and compatible with various topical prescription medications.
• In another study by Nebus et al.,²³ twenty-three babies and children (3 months to 5 years of age) were enrolled in a 4-week study.
  • Similarly, patients must have mild to moderate AD and at least 5% BSA involvement.
  • Patients applied an occlusive colloidal oatmeal cream twice daily on the entire body and a colloidal oatmeal-based glycerin cleanser for all routine bathing.
  • Patients could continue any topical prescription AD medication already in use but must discontinue any previous cleansers or moisturizers.
  • The oat-based regimen was well tolerated and significantly reduced itching by over 45% (mean) as early as week 2 of use.
  • IGA and EASI were significantly improved from baseline at both week 2 and 4.
  • Over 60% of patients were categorized as clear or almost clear by the end of the study.
  • Baby/Child Quality of Life Index was also significantly improved by week 4.
• In another clinical study,²⁴ 21 patients age 15 to 60 years with mild to moderate AD and at least 5% BSA were entered in this 14-day study.
  • Patients used the oatmeal-based body wash once daily and applied the oatmeal-based therapeutic cream to the body twice daily.
  • They were permitted to continue prescription topical treatments for AD.
  • Itching was significantly improved at weeks 1 and 2, with over 40% improvement in the mean itch score at week 1.
  • Investigator evaluations showed a significant improvement in the mean eczema severity score after 2 weeks of regimen use, with 62% of patients showing improvement from baseline.
• In a 6-week randomized, controlled study involving 173 infants under 12 months of age with moderate to severe AD, an emollient containing colloidal oatmeal was shown to reduce the use of topical steroids.²⁵
  • High-potency topical steroid usage significantly decreased by 42%
  • The SCORAD index, and infants’ and parents’ quality of life significantly improved (p < 0.0001) in both groups.

Microbiome

• The microbiome has been implicated in many different dramatological conditions.
• In AD the microbiome of lesional skin differs from that of non-lesional skin.²⁶
  • In lesional skin there tends to be less microbial diversity and we see this as lesions which are often colonized preferentially with staph aureus.
• A 14-day study with 65 adult subjects (mean age=34.5y) was conducted to look at the effects of a colloidal oatmeal cream versus a moisturizing lotion without oatmeal.²⁶
  • Subjects used assigned product to the body twice daily.
  • The study showed significant improvement in transepidermal water loss (TEWL), skin hydration as well as itch.
  • As expected, non-lesional skin had greater microbial diversity than lesional skin at both groups at baseline.
  • Over the course of the study, subjects treated with the oatmeal-based cream had increased microbial diversity of lesional skin that approached that of non-lesional skin.
  • This diversity was lost when the product was discontinued.
  • The product that did not contain oatmeal did not improve microbial diversity of lesional skin at any point during the study.

Safety

• Products containing colloidal oatmeal are very well tolerated.
  • Although more than 8 million oat-based cosmetics are sold yearly, there are very few reports of allergic contact dermatitis or contact urticaria.²⁷
  • In the very few patients with cutaneous adverse effects to topical oats the reactions are generally very mild and did not recur with repeat application.²⁸
• In a series of studies, the safety of topical products containing oatmeal were assessed for irritant and allergenic potential on repeat insult patch testing, in safety-in-use and ocular studies using subjects with non-sensitive and sensitive skin.²⁸
  • Low-level reactions were documented in 1.0% of subjects during the induction phase of repeat insult patch testing;
  • one of 2291 subjects developed a persistent but doubtful low-level reaction involving edema during the challenge phase in repeat insult patch testing.²⁸
  • No allergies were reported by 80 subjects after patch testing after in-use application.²⁸

Conclusion

Moisturizers are essential in the management of AD. Non-prescription ingredients such as colloidal oatmeal have been used for years as an adjunct to provide further benefits. There is mounting evidence that colloidal oatmeal can safely enhance skin hydration and even help resolve clinical lesions through anti-inflammatory effects and by modulation of the microbiome. Currently, there are oat-based skin products available OTC, including Aveeno by Johnson & Johnson.

Introduction

Patients often seek natural approaches to treating skin disease. Colloidal oatmeal has been used for decades to improve atopic dermatitis and soothe other pruritic and xerotic dermatologic conditions.¹ Although initially developed because of historical use, data is growing supporting its myriad benefits.

Background

Oats have long been used as treatment for skin disorders and to beautify the skin. The oldest oat grains were found in Egypt around 2000 BC^2,3 and the nutritional value of oatmeal and its topical benefits have been recognized since Roman times.^2,3,4 Oats were introduced into North America in the 17th century.² In 1945 a ready to use colloidal oatmeal for skin care became available.³ Colloidal oatmeal is produced by grinding fine granules of oatmeal and subsequently boiling it to extract the colloidal material. A colloid is a substance microscopically dispersed evenly throughout another substance.

Colloidal oatmeal was approved by the Food and Drug Administration (FDA) as a skin protectant agent for over-the-counter use in 2003.⁵ One of its approved listings is that it “temporarily protects and helps relieve minor skin irritation and itching”.⁵ It is recognized as a natural health product skin protectant ingredient by Health Canada.⁶

Atopic dermatitis (AD) is a common, chronic, pruritic skin condition with a high prevalence in children. Although AD has a complex pathogenesis there is substantial evidence that a genetically impaired skin barrier plays a role in its development.^1,7,8 The defective barrier allows irritants and antigens to penetrate leading to inflammation.⁹ Decreased stratum corneum hydration also leads to skin inflammation.¹⁰ This results in the eczematous pruritic lesions of AD.

Thus, restoration of skin barrier and stratum corneum hydration, soothing of itch and reduction of inflammation are critical for improvement of AD and quality of life for the patient and their families.¹ Moisturization and barrier protection play a central role in the treatment of AD. They are recommended as first line and adjunctive agents for the management of AD. ^11,12

Oatmeal Properties

Colloidal oatmeal has multiple properties that make it ideal for managing AD and other xerotic and pruritic skin conditions. The small particles of the oat proteins form an occlusive barrier, protecting the skin from external agents^1,13 and preventing moisture loss. It contains high concentrations of starches and beta-glucan that create an occlusive film and exhibit water-absorbing properties.¹⁴ It also has antioxidant (e.g. avenanthramides, vitamin E, ferulic acid, caffeic acid)^3,4,15 and anti-inflammatory properties.^16,17 Aventhramides are phenolic compounds with potent anti-inflammatory activity, through inhibition of NFKB in keratinocytes and inhibition of the release of the proinflammatory cytokine IL-8.¹⁸ The level of anti-inflammatory effect is similar to that of topical 1% hydrocortisone.¹⁸ Colloidal oatmeal can also act as a skin buffer, restoring the pH of the skin to normal.⁴

Efficacy

The benefits of colloidal oatmeal have been known for decades and several studies as early as the 1950s have reported the hydrating, soothing, protective and anti-irritant properties in AD.^1,19-21

In the study by Nebus et al.,²² twenty-five patients aged 12 to 60 years were enrolled in the 8-week study. Inclusion criteria included mild to moderate AD with at least 5% body surface area (BSA). They used a topical regimen of twice-daily oat-based occlusive cream and a once-daily oat-based body wash. Patients were permitted to continue their topical prescription AD treatments, however, patients on systemic medications for their AD were excluded. The results demonstrated that daily use of the adjunctive oat-based regimen significantly improved AD outcomes at all time points compared to baseline: Investigators Global Assessment (IGA), Eczema Area and Severity Index (EASI), and itching. Dermatology Life Quality Index (DLQI) was significantly improved from baseline at weeks 4 and 8. Some patients became clear of eczema as early as week 2 of use and over 45% of patients were clear or almost clear by week 8. Safety assessments revealed the regimen was well tolerated and compatible with various topical prescription medications.

In another study by Nebus et al.,²³ twenty-three babies and children (3 months to 5 years of age) were enrolled in a 4-week study. Similarly, patients must have mild to moderate AD and at least 5% BSA involvement. Patients applied an occlusive colloidal oatmeal cream twice daily on the entire body and a colloidal oatmeal-based glycerin cleanser for all routine bathing. Patients could continue any topical prescription AD medication already in use but must discontinue any previous cleansers or moisturizers. The oat-based regimen was well tolerated and significantly reduced itching by over 45% (mean) as early as week 2 of use. IGA and EASI were significantly improved from baseline at both week 2 and 4. Over 60% of patients were categorized as clear or almost clear by the end of the study. Baby/Child Quality of Life Index was also significantly improved by week 4.

In another clinical study,²⁴ 21 patients age 15 to 60 years with mild to moderate AD and at least 5% BSA were entered in this 14-day study. Patients used the oatmeal-based body wash once daily and applied the oatmeal-based therapeutic cream to the body twice daily. They were permitted to continue prescription topical treatments for AD. Itching was significantly improved at weeks 1 and 2, with over 40% improvement in the mean itch score at week 1. Investigator evaluations showed a significant improvement in the mean eczema severity score after 2 weeks of regimen use, with 62% of patients showing improvement from baseline.

In a 6-week randomized, controlled study involving 173 infants under 12 months of age with moderate to severe AD, an emollient containing colloidal oatmeal was shown to reduce the use of topical steroids.²⁵ High-potency topical steroid usage significantly decreased by 42%. The SCORAD index, and infants’ and parents’ quality of life significantly improved (p < 0.0001) in both groups.

Microbiome

The microbiome has been implicated in many different dramatological conditions. In AD the microbiome of lesional skin differs from that of non-lesional skin.²⁶ In lesional skin there tends to be less microbial diversity and we see this as lesions which are often colonized preferentially with staph aureus. A 14-day study with 65 adult subjects (mean age=34.5y) was conducted to look at the effects of a colloidal oatmeal cream versus a moisturizing lotion without oatmeal.²⁶ Subjects used assigned product to the body twice daily. The study showed significant improvement in transepidermal water loss (TEWL), skin hydration as well as itch. As expected, non-lesional skin had greater microbial diversity than lesional skin at both groups at baseline. Over the course of the study, subjects treated with the oatmeal-based cream had increased microbial diversity of lesional skin that approached that of non-lesional skin. This diversity was lost when the product was discontinued. The product that did not contain oatmeal did not improve microbial diversity of lesional skin at any point during the study.

Safety

Products containing colloidal oatmeal are very well tolerated. Although more than 8 million oat-based cosmetics are sold yearly, there are very few reports of allergic contact dermatitis or contact urticaria.²⁷ In the very few patients with cutaneous adverse effects to topical oats the reactions are generally very mild and did not recur with repeat application.²⁸

In a series of studies, the safety of topical products containing oatmeal were assessed for irritant and allergenic potential on repeat insult patch testing, in safety-in-use and ocular studies using subjects with non-sensitive and sensitive skin.²⁸

Low-level reactions were documented in 1.0% of subjects during the induction phase of repeat insult patch testing; one of 2291 subjects developed a persistent but doubtful low-level reaction involving edema during the challenge phase in repeat insult patch testing.²⁸ No allergies were reported by 80 subjects after patch testing after in-use application.²⁸

Conclusion

Moisturizers are essential in the management of AD. Nonprescription ingredients such as colloidal oatmeal have been used for years as an adjunct to provide further benefits. There is mounting evidence that colloidal oatmeal can safely enhance skin hydration and even help resolve clinical lesions through anti-inflammatory effects and by modulation of the microbiome. Currently, there are oat-based skin products available OTC, including Aveeno by Johnson & Johnson.

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ABSTRACT
Acitretin over the last 20 years has proven useful in a number of dermatologic diseases. Evidence of efficacy, side-effect profile, and approach to its use will be reviewed.

Key Words:
acitretin, congenital ichthyosis, Darier disease, keratodermas, lichen planus, lichen sclerosus, lupus erythematosus, malignancy, pityriasis rubra pilaris, psoriasis

Acitretin is a synthetic oral retinoid that has been used by dermatologists over the last two decades for a number of cutaneous diseases. It replaced etretinate (the prodrug) in the late 1980’s (1998 in the United States), because acitretin presents a more favorable pharmacokinetic profile. The British Association of Dermatologists has recently produced comprehensive guidelines on the efficacy and use of acitretin in dermatology.¹ With this recent development, a further examination of acitretin and its therapeutic application in a wide array of cutaneous diseases is warranted.

Chemistry and Mechanism of Action

Retinoids deliver their biological effects through two members of the steroid/thyroid super family of nuclear hormone receptors: first, the retinoic acid receptors (RAR á, â, ã) and second, the retinoid X receptor (RXR á, â, ã).^2-4 Acitretin is a second generation retinoid that activates all three RAR subtypes. Etretinate is an ethyl ester prodrug that is converted into the active metabolite acitretin. Acitretin’s effects are thought to be induced by binding to nuclear receptors of genes, controlling cellular differentiation and proliferation, reducing inflammation and keratinization, and inhibiting neutrophil chemotaxis.⁵

Pharmokinetics and Metabolism

Actitretin is the main active metabolite of etretinate.⁵ Etretinate is a lipophilic drug with a half-life of approximately 120 days as compared with acitretin, which has a half-life of approximately 50 hours.⁶ Etretinate can be detected in the serum for up to 2 years post cessation of treatment. Acitretin, with concurrent ethanol consumption, can result in transesterification of acitretin to etretinate.^6,7 Acitretin is a US FDA Pregnancy Category X medication and should not be administered to women of child bearing age who may wish to become pregnant during treatment and within 3 years of discontinuation of the drug.⁵ Patients are advised to take acitretin with food as this can enhance absorption and bioavailability two- to five-fold.^6,8

Efficacy in Psoriasis

There are four randomized controlled trials (RCT) comparing acitretin and etretinate, four RCTs comparing acitretin with placebo and one open study.^9-16 These studies contain a heterogeneous grouping of generalized pustular, severe, and erythrodermic variants in conjunction with plaque type psoriasis. In addition, these studies preceded the new standardized PASI 75
outcome measure (i.e., 75% improvement from baseline in Psoriasis Area Severity Index score). Nevertheless, a retrospective post hoc analysis of the data would suggest 52% of the patients achieving PASI 75 and 85% achieving PASI 50 after 12 weeks (per protocol analysis) of treatment.¹⁷

In the open trial (Canadian), a total of 46% of patients achieved PASI 75 response and 76% PASI 50 response by the end of treatment (intent to treat average duration of 267 days).18 Higher doses (50-75mg daily) were found to be more effective, however, these produced more side-effects. Furthermore, acitretin has demonstrated greater efficacy in pustular and erythrodermic psoriasis than in chronic plaque psoriasis.¹⁹

Combination Therapy in Psoriasis

Acitretin and Psoralen + Ultraviolet A (PUVA)

Four RCTs compared acitretin and PUVA.⁴ These studies showed the acitretin + PUVA combination was more effective than PUVA alone.⁴ It reduced the overall number of PUVA treatments.⁶ This, in conjunction with acitretin’s demonstrated preventative action against carcinogenesis, allows for theoretical advantages.^1,7

Acitretin and Ultraviolet B (UVB)

One RCT, two open studies, along with one retrospective investigation demonstrated better outcomes and sparing of UVB in the combination group.^20-25

Acitretin and Calcipotriol Ointment

Two RCTs showed additive benefits of acitretin and calcipotriol
ointment in combination.²⁶ In one study, the ‘clear’ or ‘almost clear’
success rate increased to 67% with the addition of calcipotriol (vs.
41% with acitretin monotherapy).²⁷ In the second study, patients’
complete clearance increased from 15% to 40% after 12 weeks.²⁸

Palmoplantar Pustulosis

Two RCTs compared acitretin with placebo.^29-30 Acitretin produced
a five-fold reduction in pustules after 4 weeks and a ten-fold
reduction in pustules after 12 weeks.³⁰

Nail Psoriasis

In one open study, patients (N = 36) with nail psoriasis were
treated with acitretin doses of 0.2-0.3mg/kg given daily for
6 months.31 The findings showed a 41% mean improvement on
the Nail Psoriasis Severity Index (NAPSI). In addition, 25% of
patients were cleared or almost cleared.

Review of Indications and Level of Evidence1

Table 1 and Table 2 provide brief overviews of studies investigating
the use of acitretin in various skin disorders and their quality of
supporting evidence.

Safety and Tolerability

Acitretin has a side-effect profile similar to other systemic
retinoids. Many of the reported adverse effects (Table 3)
have occurred in patients using higher doses (>25mg/day)
of acitretin and are less prevalent in low doses of acitretin
(<25mg/day).

Prescribing

Therapy should be initiated only under the responsibility of a
supervising dermatologist.1 It is recommended that capsules be
taken once daily with fatty foods.⁴⁶ Therapeutic and toxic doses
of acitretin are dose-dependent, and individual adjustments
of dosage is necessary. Effective doses are typically around
25-50mg/day.^47,48 Researchers state that a gradual escalation
approach is most effective.⁴⁸ Acitretin dosages are recommended
to start at 25mg/day and increase by 10-25mg every 2-4 weeks
to achieve the maximally tolerated dose.¹ It is important to note
that the response to acitretin is gradual, typically requiring
3-6 months to reach peak effectiveness.¹ In Darier disease a
starting dose of 10mg daily may be appropriate.¹

Monitoring

Patients taking acitretin require monthly monitoring for the first
3 months, then every 3 months thereafter. A complete blood count
(CBC) is required as well as a fasting lipid profile (TG, cholesterol).
Liver function (AST, ALT) and blood sugar levels of diabetic
patients must also be monitored.1 Radiological investigation for
skeletal changes need not be done routinely.¹

Conclusion

The use of acitretin over the last 20 years has proven to be an
effective treatment and adjunct in a number of dermatological
conditions. A thorough understanding of the drug, its efficacy,
and potential side-effects is important for yielding a beneficial
therapeutic outcome for patients.

References

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2. Chandraratna RA. Rational design of receptor-selective retinoids. J Am Acad Dermatol 39(4 Pt 2):S124-8 (1998 Oct).
3. Kang S, Li XY, Voorhees JJ. Pharmacology and molecular action of retinoids and vitamin D in skin. J Investig Dermatol Symp Proc 1(1):15-21 (1996 Apr).
4. Rowe A. Retinoid X receptors. Int J Biochem Cell Biol 29(2):275-8 (1997 Feb).
5. Pang ML, Murase JE, Koo J. An updated review of acitretin–a systemic retinoid for the treatment of psoriasis. Expert Opin Drug Metab Toxicol 4(7):953-64 (2008 Jul).
6. Stiefel Laboratories. Soriatane (acitretin) prescribing information. Stiefel Laboratories, Inc., Coral Gables, FL: USA (2007).
7. Larsen FG, Jakobsen P, Knudsen J, et al. Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol. J Invest Dermatol 100(5):623-7 (1993 May).
8. McNamara PJ, Jewell RC, Jensen BK, et al. Food increases the bioavailability of acitretin. J Clin Pharmacol 28(11):1051-5 (1988 Nov).
9. Kragballe K, Jansen CT, Geiger JM, et al. A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis. Results of a Nordic multicentre study. Acta Derm Venereol 69(1):35-40 (1989).
10. Gollnick H, Bauer R, Brindley C, et al. Acitretin versus etretinate in psoriasis. Clinical and pharmacokinetic results of a German multicenter study. J Am Acad Dermatol 19(3):458-68 (1988 Sep).
11. Meffert H, Sonnichsen N. Acitretin in the treatment of severe psoriasis: a randomized double-blind study comparing acitretin and etretinate. Acta Derm Venereol Suppl (Stockh) 146:176-7 (1989).
12. Ledo A, Martin M, Geiger JM, et al. Acitretin (Ro 10-1670) in the treatment of severe psoriasis. A randomized double-blind parallel study comparing acitretin and etretinate. Int J Dermatol 27(9):656-60 (1988 Nov).
13. Goldfarb MT, Ellis CN, Gupta AK, et al. Acitretin improves psoriasis in a dosedependent fashion. J Am Acad Dermatol 18(4 Pt 1):655-62 (1988 Apr).
14. Lassus A, Geiger JM, Nyblom M, et al. Treatment of severe psoriasis with etretin (RO 10-1670). Br J Dermatol 117(3):333-41 (1987 Sep).
15. Gupta AK, Goldfarb MT, Ellis CN, et al. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol 20(6):1088-93 (1989 Jun).
16. Olsen EA, Weed WW, Meyer CJ, et al. A double-blind, placebo-controlled trial of Acitretin for the treatment of psoriasis. J Am Acad Dermatol 21(4 Pt 1):681-6 (1989 Oct).
17. Geiger JM. Efficacy of acitretin in severe psoriasis. Skin Therapy Lett 8(4):1-3, 7 (2003 Apr-May).
18. Murray HE, Anhalt AW, Lessard R, et al. A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter study. J Am Acad Dermatol 24(4): 598-602 (1991 Apr).
19. Magis NL, Blummel JJ, Kerkhof PC, et al. The treatment of psoriasis with etretinate and acitretin: a follow up of actual use. Eur J Dermatol 10(7):517-21 (2000 Oct-Nov).
20. Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalized pustular psoriasis: a multicenter study in Japan. J Dermatol 26(3):141-9 (1999 Mar).
21. Iest J, Boer J. Combined treatment of psoriasis with acitretin and UVB phototherapy compared with acitretin alone and UVB alone. Br J Dermatol 120(5):665-70 (1989 May).
22. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis. Arch Dermatol 126(4):482-6 (1990 Apr).
23. Lowe NJ, Prystowsky JH, Bourget T, et al. Acitretin plus UVB therapy for psoriasis. Comparisons with placebo plus UVB and acitretin alone. J Am Acad Dermatol 24(4):591-4 (1991 Apr).
24. Kampitak T, Asawanonda P. The efficacy of combination treatment with narrowband UVB (TL-01) and acitretin vs narrowband UVB alone in plaque-type psoriasis: a retrospective study. J Med Assoc Thai 89 (Suppl 3):S20-4 (2006 Sep).
25. Ozdemir M, Engin B, Baysal I, et al. A randomized comparison of acitretin-narrow-band TL-01 phototherapy and acitretin-psoralen plus ultraviolet A for psoriasis. Acta Derm Venereol 88(6):589-93 (2008).
26. van de Kerkhof PC. Topical use of calcipotriol improves the outcome in acitretin treated patients with severe psoriasis vulgaris. Br J Dermatol 135(Suppl 47):30 (Abstract) (1996).
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28. Rim JH, Park JY, Choe YB, et al. The efficacy of calcipotriol + acitretin combination therapy for psoriasis: comparison with acitretin monotherapy. Am J Clin Dermatol 4(7):507-10 (2003).
29. Schroder K, Zaun H, Holzmann H, et al. Pustulosis palmo-plantaris. Clinical and histological changes during etretin (acitretin) therapy. Acta Derm Venereol Suppl (Stockh) 146:111-6 (1989).
30. Lassus A, Geiger JM. Acitretin and etretinate in the treatment of palmoplantar pustulosis: a double-blind comparative trial. Br J Dermatol 119(6):755-9 (1988 Dec).
31. Tosti A, Ricotti C, Romanelli P, et al. Evaluation of the efficacy of acitretin therapy for nail psoriasis. Arch Dermatol 145(3):269-71 (2009 Mar).
32. Laurberg G, Geiger JM, Hjorth N, et al. Treatment of lichen planus with acitretin. A double-blind, placebo-controlled study in 65 patients. J Am Acad Dermatol 24(3):434-7 (1991 Mar).
33. van Dooren-Greebe RJ, van de Kerkhof PC, Happle R. Acitretin monotherapy in Darier’s disease. Br J Dermatol 121(3):375-9 (1989 Sep).
34. Thestrup-Pedersen K, Andersen KE, Menne T, et al. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single-blind placebo-controlled study. Acta Derm Venereol 81(5):353-5 (2001 Oct-Nov).
35. Hardin J, Mydlarski PR. Systemic retinoids: chemoprevention of skin cancer in transplant recipients. Skin Therapy Lett 15(7):1-4 (2010 Jul-Aug).
36. Vanderveen EE, Ellis CN, Campbell JP, et al. Methotrexate and etretinate as concurrent therapies in severe psoriasis. Arch Dermatol 118(9):660-2 (1982 Sep).
37. Ruzicka T, Sommerburg C, Goerz G, et al. Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine. Br J Dermatol 127(5):513-8 (1992 Nov).
38. Ruzicka T, Meurer M, Bieber T. Efficiency of acitretin in the treatment of cutaneous lupus erythematosus. Arch Dermatol 124(6):897-902 (1988 Jun).
39. Chapalain V, Beylot-Barry M, Doutre MS, et al. Treatment of pityriasis rubra pilaris: a retrospective study of 14 patients. J Dermatolog Treat 10(2):113-7 (1999 Jan).
40. Bousema MT, Romppanen U, Geiger JM, et al. Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: a double-blind, placebo-controlled study. J Am Acad Dermatol 30(2 Pt 1):225-31 (1994 Feb).
41. Lacour M, Mehta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol 134(6):1023-9 (1996 Jun).
42. Blanchet-Bardon C, Nazzaro V, Rognin C, et al. Acitretin in the treatment of severe disorders of keratinization. Results of an open study. J Am Acad Dermatol 24(6 Pt 1):982-6 (1991 Jun).
43. Bruckner-Tuderman L, Sigg C, Geiger JM, et al. Acitretin in the symptomatic therapy for severe recessive x-linked ichthyosis. Arch Dermatol 124(4):529-32 (1988 Apr).
44. Kullavanijaya P, Kulthanan K. Clinical efficacy and side effects of acitretin on the disorders of keratinization: a one-year study. J Dermatol 20(8):501-6 (1993 Aug).
45. Happle R, van de Kerkhof PC, Traupe H. Retinoids in disorders of keratinization: their use in adults. Dermatologica 175(Suppl 1):107-24 (1987).
46. DiGiovanna JJ, Gross EG, McClean SW, et al. Etretinate: effect of milk intake on absorption. J Invest Dermatol 82(6):636-40 (1984 Jun).
47. Ling MR. Acitretin: optimal dosing strategies. J Am Acad Dermatol 41(3 Pt 2):S13-7 (1999 Sep).
48. Geiger JM, Czarnetzki BM. Acitretin (Ro 10-1670, etretin): overall evaluation of clinical studies. Dermatologica 176(4):182-90 (1988).

1. Division of Dermatology, University of Toronto, Toronto, ON, Canada
2. Faculty of Medicine, University of Toronto, Toronto, ON, Canada
3. University Health Network (Western Division), Toronto, ON, Canada

Introduction

Atopic dermatitis (AD) or eczema is a chronic, relapsing form of skin inflammation that is attributable to multiple pathogenic, genetic, and environmental factors, as well as a dysfunctional epidermal barrier. Immune responses involved in AD culminate in dry skin, pruritus, and IgE mediated sensitization to food and environmental allergens.¹ An improved understanding of crucial skin barrier defenses and the inflammatory cascade that drives disease activities has led clinicians to reassess conventional approaches to treatment and recognize emollients for their therapeutic potential. Accordingly, emollient-based moisturizers and cleansers have been established as essential adjuvants for successful AD management.

Background

AD is very common.

• Prevalence is estimated at 15%-30% in children and 2%-10% in adults.²
• In 85% of AD-afflicted children, onset of disease occurs before the age of 5 years.³
• Up to 70% of children experience a spontaneous remission before adolescence.⁴

AD is associated with a marked decrease in skin barrier function due to endogenou factors.

• Increasing evidence implicates one of the primary causes of AD as a genetic defect in the epidermis that permits the infiltration of allergens, environmental irritants, and microbes, thus inducing inflammatory responses.⁵
• A defective skin barrier prohibits the necessary levels of antimicrobial peptides to form in the epidermis in order to protect against infectious agents, such as Staphylococcus aureus (S. aureus).

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The Role of Moisturizers in Optimal AD Management

A persistent feature of AD is dry skin that is caused by a combination of intrinsic disease mechanisms and hyperreactivity to exogenous factors. Some treatments for AD can further exacerbate xerosis, itching, and irritation. Such external insults on an already impaired skin barrier drive the dry skin cycle and leave skin vulnerable to microbial infections. For these reasons, maintaining hydration and restoring epidermal barrier defenses provide the rationale for moisturization therapy.

What are Moisturizers?

• Moisturizers are composed of a combination of key ingredients that are categorized as emollients, humectants, and occlusives, which work synergistically to enhance hydration and barrier function.
• A randomized controlled study showed that well-designed formulations incorporating these constituents can improve the epidermal barrier function and increase skin hydration levels; however, the effects are determined by individual product composition.^6,7

How do Moisturizers Work?

• The mechanism of action of emollients may be elucidated as a role substitution by lipid ingredients, which take on the functions of naturally occurring lipids that are either absent or impaired in eczematous skin.
• Treatment of the skin with moisturizers can repair the skin barrier, increase water content, reduce transepidermal water loss (TEWL), and restore the lipid barriers’ ability to attract, retain, and redistribute water.
  • Maximum effects are derived from prophylactic and frequent use.
  • Moisturizers maintain hydration in the skin by slowing TEWL. In doing so, they help dry and/or aging skin to improve its structural integrity, appearance, and tactile properties.
• By covering tiny fissures in the skin and providing an occlusive protective film over the stratum corneum (SC), moisturizers restore the epidermal barrier and reduce the penetrability of allergens and irritants.

Moisturizers Demonstrate Adjuvant Properties

• Regimented moisturization has become standard adjunctive AD therapy by serving as a foundation to support pharmacologic measures, reducing the need for topical corticosteroids and calcineurin inhibitors, and mitigating the side-effects from medications.
• During flares, OTC combination preparations containing a moisturizer with a topical corticosteroid (e.g., clobetasone and hydrocortisone) are helpful to control inflammation and restore the skin barrier.

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Essential Components of Effective Moisturizers

Emollients

• Emollients are mainly lipids and oils that hydrate and improve the appearance of the skin by contributing to softness, smoothness, and improved flexibility (Table 1).
  • The lubricity of some moisturizers can influence consumer satisfaction and product preference.
• The SC of AD patients have significantly reduced levels of ceramides (lipid molecules), which are important components of skin structure.
• The topical replacement of lipids serves to ‘fill the cracks’ between clusters of desquamating corneocytes.

Humectants

• Humectants attract and retain hydration in the skin by enhancing water absorption from the dermis into the epidermis, or by absorbing water from the external environment (Table 2).
• Many humectants also have emollient-like properties.⁷
• The most effective humectant is the trihydroxylated molecule, glycerin, which is also commonly referred to as glycerol.
  • Glycerin is the most widely used humectant.
  • A double-blind study comparing glycerin with urea showed that although both compounds were equally effective in treating xerosis, glycerin caused significantly less adverse skin reactions.⁸
• Urea is another commonly used humectant that is effective against TEWL.
  • Avoid the use of urea-containing moisturizers in young children due to irritation.

Occlusives

• Occlusives reduce TEWL by creating a hydrophobic barrier over the skin and contributing to the matrix between corneocytes (Table 3).
• Efficacy is enhanced when occlusives are applied to slightly dampened skin.
• Their main limitations include odour, potential allergenicity, and a ‘greasy’ feel.
• Petroleum jelly (petrolatum), in a minimum concentration of 5%, is the most effective occlusive, followed by lanolin, mineral oil, and silicones.
• Silicone-based derivatives (e.g., dimethicone) are oil-free alternatives that are noncomedogenic, nonirritating, nonsensitizing, and more cosmetically acceptable.

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Recommendations for Use

The following adapted guidelines for the use of moisturizers in AD, developed by the National Institute for Health and Clinical Excellence,⁹ serve as practical advice for patients and their doctors.

• Physicians should be prepared to offer patients a choice of unperfumed emollients:
  • suited to their individual needs and preferences.
  • for everyday moisturizing, as well as emollient-enriched washing and bathing formulations.
• Moisturizers should be:
  • used more often and in larger amounts than other treatments.
  • used even when AD is clear.
  • used while using other treatments.
  • offered as a single or combination product (offer alternatives if one formulation causes irritation or does not gain patient acceptance).
  • easy to apply throughout the day.
• Recommend leave-on moisturizers in large quantities.
• Instruct patients or their parents on sufficient and proper application.
• When multiple topical products are used concurrently, instruct patients to apply them one at a time, allowing for several minutes to pass in-between applications.
• Consider increasing the use of emollients if patients report difficulties in controlling itch.

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Mild Skin Cleansers

The regular use of mild cleansers is an important aspect of optimal AD management. Not only is cleansing an essential part of basic hygiene, but it also removes dirt, sweat, bacteria, and exfoliated cells, which prepares the skin to receive topical medications and improves drug absorption.

• AD lesions are commonly colonized with S. aureus. Routine cleansing can enhance antimicrobial activity against S. aureus and decrease the chances of infection.
• Care must be taken to minimize any further weakening of the SC barrier during cleansing. The use of improper techniques and unsuitable cleansing agents on the face or body can initiate flares or exacerbate AD.
  • The use of anionic detergents (i.e., soaps) can alter the pH of skin, resulting in increased sensitivity to irritants and conditions that can promote bacterial proliferation.¹⁰
  • While removing excess sebum, cleansers can also inadvertently damage intercellular lipids, which can lead to further impairment of the barrier function and cause dry skin.
• Cleansers that are suitable for eczematous skin are generally based on mild synthetic surfactants that cause minimal barrier disturbances.
  • Non-ionic surface-acting agents (e.g., silicone and polysorbate) are less likely to cause irritation and are pH-compatible with the skin.
  • Silicone surfactants, such as dimethicone, are effective at eliminating surface debris without completely stripping away protective oils.
  • Emollients contained in cleansers can minimize barrier damage by emulsifying dirt and oil for easy removal, while at the same time replacing lipids that are lost during the washing process.¹¹

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Using the 4 Rs of AD Management

The best practice management of AD must include patient education. Pharmacists are encouraged to provide verbal and written information on AD and selected treatments, as well as practical demonstrations of proper administration. Remembering the 4 Rs can help to simplify the multi-layered approach for management.

Recognize

• Recognize and diagnose the condition promptly in order for treatment to be initiated.
• AD patients have a predisposition for developing other atopic conditions, such as asthma and allergic rhinitis.¹
• Encourage patients to maintain a diary to track foods eaten, flares, and the use of medications, moisturizers, and cleansers, which can guide therapeutic decision-making.

Remove

• Avoidance is a central AD management strategy. Identify and eliminate relevant triggers (e.g., irritants, aeroallergens, and foods) and seek ways to reduce stress.
• Mild cleanser use can help to remove surface dirt, irritants, and microbes.
• Consider allergy testing to identify triggers.

Restore

• The regimented use of emollients can partially repair and restore the skin barrier and reduce infections and allergic reactivity.
• Body washes incorporating nonirritating surfactants, emollients, and humectants can replenish barrier lipids during cleansing to minimize TEWL. Lukewarm baths (5-10 minutes in duration) are recommended over showers.
• Creams and ointments are more effective for eczematous skin. Apply moisturizers 3-5 minutes after bathing.

Regulate

• When flares occur, interrupt and regulate inflammatory responses with immediate treatment in order to break the itch-scratch cycle and limit AD severity.
• Therapeutic strategies include topical corticosteroids, topical calcineurin inhibitors, antimicrobials, and oral antihistamines, as well as routine skin care.
• In patients exhibiting an inadequate response to therapy, assess treatment adherence, side-effects, and review moisturizer and cleanser use.

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Conclusion

Due to the chronicity of AD, as well as multiple factors contributing to its etiology, successful management requires a multipronged approach that includes lifestyle modifications, adaptations to skin care practices, and medical intervention. Although topical corticosteroids are firmly established as the cornerstone therapy, long-term and overuse are associated with skin atrophy and adverse systemic effects. The combination of moisturizers with topical steroids can have a significant steroid-sparing effect, especially in children with mild-to-moderate AD. A therapeutic approach that incorporates patient education and emollient therapy can complement pharmacologic measures to extend periods of remission and significantly lessen the disease burden.

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References

1. Bieber T. N Engl J Med 358(14):1483-94 (2008 Apr 3).
2. Williams H, et al. J Allergy Clin Immunol 118(1):209-13 (2006 Jul).
3. Beltrani VS, et al. Dermatol Online J 9(2):1 (2003 Mar).
4. Illi S, et al. J Allergy Clin Immunol 113(5):925-31 (2004 May).
5. Kisich KO, et al. J Allergy Clin Immunol 122(1):62-8 (2008 Jul).
6. Buraczewska I, et al. Br J Dermatol 156(3):492-8 (2007 Mar).
7. Del RossJQ. Cosmeceutical moisturizers. In: Draelos ZD, ed. Procedures in cosmetic dermatology series: cosmeceuticals. 1st ed. Philadelphia: Elsevier p97-102 (2005).
8. Loden M, et al. Acta Derm Venereol 82(1):45-7 (2002).
9. National Institute for Health and Clinical Excellence. Atopic eczema in children (2007 Dec).
10. Draelos ZD. Dermatol Clin 18(4):597-607 (2000 Oct).
11. Cork MJ. J Dermatolog Treat 8(Suppl 1):S7-13 (1997).

¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, Sunnybrook Hospital, University of Toronto, Toronto, ON, Canada

ABSTRACT

There exists a multitude of medical conditions that cause intractable itch, or pruritus. The successful management of this symptom depends explicitly on establishing the underlying cause. Studies have shown that drugs not traditionally used in the treatment of cutaneous disorders, such as opiate receptor antagonists, antidepressants, and antiepileptics, can provide symptomatic relief of intractable itch. These novel antipruritic agents will be explored in this review.

Key Words:
Intractable itch, pruritus, opiate receptor antagonists, antidepressants, anticonvulsants, antihistamine, phototherapy, thalidomide

Itch, or pruritus, refers to an unpleasant sensation in the skin that provokes scratching. Arguably, all humans experience an itch at some point in their lives. One-fifth of the population is thought to suffer from some form of itch at any given moment.¹ The intensity of pruritus ranges from mild to severe, and can have a significant psychosocial impact on patients, by interfering with their sleep and daily activities. Itch is one of the most common symptoms associated with cutaneous disorders that require treatment from dermatologists.

Its management presents a treatment challenge, as many therapies are often tried to no avail.

Causation can sometimes be easily established, such as a primary dermatological disease (e.g., atopic dermatitis, psoriasis, urticaria), underlying renal or hepatic disease, or a drug-induced reaction (e.g., opiates). However, in many cases resolution of the symptom does not follow even after the etiology has been established; this is especially true for chronic disorders.
Tables 1 and 2 summarize dermatologic and systemic disorders that can cause intractable itch.

Pathophysiology

The neuropathways responsible for relaying pruritus to the brain are well-known. The itch sensation is carried to the brain by a dedicated subset of nociceptive C neurons. Like the pathways for pain and temperature, the message is relayed to the spinal cord, then crosses the midline and ascends via the lateral spinothalamic tract to the thalamus, and then finally travels to the cerebral cortex.

There are many peripheral mediators of pruritus, which include histamine, cytokines (IL-2), tryptase, substance P, serotonin, and opioid peptides. The most potent from this list is histamine, which is released by dermal mast cells via many triggers (i.e., IgE crosslinking, substance P, complement C5a). This biogenic amine acts mainly as a neurotransmitter and plays a major role in skin reactions associated with urticaria, urticaria pigmentosa, and insect bites. Its role in other skin diseases (e.g., atopic dermatitis) is debatable.

Traditional Topical Agents

Topical agents provide symptomatic relief. However, it must be stressed that successful management depends on establishing the underlying physiologic imbalance.

• Menthol 1%, compounded in an aqueous cream or in a moisturizer base, sensitizes thermal receptors to cold and is considered a safe remedy that has been used for centuries.
• Doxepin 5% cream is a topical tricyclic antidepressant that relieves pruritic symptoms associated with atopic dermatitis. Patients being treated with doxepin should be cautioned regarding adverse side-effects, such as systemic absorption and drowsiness.
• Capsaicin 0.025%-0.3% cream is derived from chili peppers, and triggers the release of substance P from C nociceptors, which desensitizes nerve fibers. Local irritation can result.
• Topical corticosteroids are only considered when there is a primary dermatosis, due to the potential for local side-effects (i.e., telangiectasia, atrophy, striae).
• Topical anesthetics are seldom used as they are associated with an increased risk of allergic sensitization.
• Other topical agents that may be of benefit include: moisturizers, oatmeal-based agents, calamine lotion, aloe and camphor.

Systemic Agents

Systemic agents are tried if there is a specific indication or if the more conservative measures are ineffective. Antihistamines are predominantly used for treating urticaria, but are otherwise rarely effective for itch. The first generation antihistamines are sedating, but are generally considered to be the most effective when compared with its subsequent counterparts. Due to its potential to affect performance, sedating antihistamines should be administered at night. The addition of successive generations (second or third) may be helpful for daytime relief as they are minimally sedating. Tranquilizers have been used, but they only serve to sedate the patient and do not directly address the pruritic symptoms.

Phototherapy

For patients who are unresponsive to traditional topical or systemic therapies, UV light (UVB or PUVA) may be an option. For example, UVB has been shown to be of benefit in the treatment of pruritus associated with chronic renal disease.² After 2 weeks of three treatments per week, improvement can be seen. If no improvement is detected following this treatment regimen, phototherapy should be reconsidered. Clinical experience seems to indicate that maintenance therapy is not required.

Novel Agents

In the past, if traditional agents were not effective, dermatologists had few other options. The emergence of a new understanding of the pathophysiology of itch has led to novel uses of existing therapies to treat pruritus, which include opiate receptor antagonists, antidepressants, and antiepileptics. The addition of these drugs to the dermatologist’s therapeutic arsenal provides options to patients who are inadequate responders to traditional agents. Table 3 provides a summary of these unconventional antipruritic agents.

Conclusions

Pruritus is a very common symptom that is associated with many dermatologic and systemic conditions, and can be challenging to treat. Conventional therapies such as topical agents and antihistamines are often not effective. Novel therapies such as opioid antagonists, antidepressants, and anticonvulsants are emerging as promising treatments for intractable itch.

References

1. Rea JN, Newhouse ML, Halil T. Skin disease in Lambeth. A community study of prevalence and use of medical care. Br J Prev Soc Med 30(2):107-14 (1976 Jun).
2. Seckin D, Demircay Z, Akin O. Generalized pruritus treated with narrowband UVB. Int J Dermatol 46(4):367-70 (2007 Apr).
3. Dunteman E, Karanikolas M, Filos KS. Transnasal butorphanol for the treatment of opioid-induced pruritus unresponsive to antihistamines. J Pain Symptom Manage 12(4):255-60 (1996 Oct).
4. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54(3):527-31 (2006 Mar).
5. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113(4):1264-9 (1997 Oct).
6. Metze D, Reimann S, Beissert S, et al. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal disease and dermatological diseases. J Am Acad Dermatol 41(4):533-9 (1999 Oct).
7. Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 56(6):979-988 (2007 Jun).
8. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552-4 (1996 Dec 7).
9. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 16(2):121-4 (1998 Aug).
10. Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood 99(7):2627 (2002 Apr 1).
11. Zylicz Z, Krajnik M, Sorge AA, et al. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage 26(6):1105-12 (2003 Dec).
12. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98(12):2736-41 (2003 Dec).
13. Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J Am Acad Dermatol 50(6):889-91 (2004 Jun).
14. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for pruritus. J Pain Symptom Manage 25(3):288-91 (2003 Mar).
15. Bueller HA, Bernhard JD, Dubroff LM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol 13(3):227-8 (1999 Nov).
16. Winhoven SM, Coulson IH, Bottomley WW. Brachioradial pruritus: response to treatment with gabapentin. Br J Dermatol 150(4):786-7 (2004 Apr).
17. Taylor RS. Multiple sclerosis potpourri. Paroxysmal symptoms, seizures, fatigue, pregnancy, and more. Phys Med Rehabil Clin N Am 9(3):551-9 (1998 Aug).
18. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 19(12):3137-9 (2004 Dec).
19. Bergasa NV, McGee M, Ginsburg IH, et al. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology 44(5):1317-23 (2006 Nov).
20. Alfadley A, Al-Hawasawi K, Thestrup-Pedersen K, et al. Treatment of prurigo nodularis with thalidomide: a case report and review of the literature. Int J Dermatol 42(5):372-5 (2003 May).
21. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Derm Venereol 80(1):24-5 (2000 Jan-Feb).

Introduction

A good skin care regimen including both prescription and non-prescription treatments
for multiple dermatological conditions is very important. Many skin disorders can
be caused by a primary dermatological condition but one should remember systemic
diseases and drugs prescribed for other conditions can also cause skin problems. Daily
skin care is a key component of management for many skin diseases. It is important to
educate patients about behavioral changes they can make on a daily basis, in addition
to prescribed therapy.

Dry Skin

Dermatological Causes

• Atopic dermatitis
• Asteatotic dermatitis
• Ichthyoses
• Irritant contact dermatitis
• Acne vulgaris
• Rosacea
• Retinoid-induced irritant dermatitis
• Psoriasis
• Cosmetic therapies & procedures

Systemic Causes

• Renal failure
• Diabetes
• Hypothyroidism
• Malnutrition

Therapeutic Causes

• Systemic retinoids (e.g., isotretinoin [Accutane^®])
• Epidermal growth factor receptor inhibitors (e.g., cetuximab [Erbitux^®])
• Radiation therapy, chemotherapy

Adjunctive Treatment

Patient education

• Learn how to recognize flares and
• treat early

Bathing

• Baths are recommended more than showers, lukewarm water, 5-10 minutes, once or twice daily.
• Use a mild cleansing product (e.g., Cetaphil^® Cleanser, Toleriane^® Cleanser).
• Add emulsifying oil (e.g., Keri® Bath Oil).

Laundry

• Mild detergents with no fragrance
• No bleach or fabric softener

Skin care

• Use mild cleansing agents.
• Apply moisturizer 3-5 minutes after bathing.
• Avoid light lotions; use products
  rich in essential fatty acids, and
  those formulated with appropriate
  combination of humectants,
  emollients, and occlusives.

Environmental avoidance

• Avoid rough fabrics, chlorine, solvents, and stress.

Itchy Skin

Dermatological Causes

Localized

• Atopic dermatitis
• Urticaria
• Insect bites
• Lichen planus
• Lichen simplex chronicus
• Psoriasis

Generalized

• Winter itch
• Infestations (e.g., lice, scabies)
• Pruritus of senescent skin

Systemic Causes

• Renal failure
• Hepatic disease (obstructive biliary disease)
• Endocrine/metabolic (hyper/hypothyroidism, diabetes, gout)
• Neurologic (multiple sclerosis, post-herpes zoster, depression, peripheral nerve injuries)
• Neoplastic (leukemia, lymphoma, multiple myeloma, internal malignant tumors)
• Hematologic (hemochromatosis, iron deficiency anemia)
• Infectious (HIV, hepatitis C)

Therapeutic Causes

• Opiates
• ASA
• Drug reactions (exanthematous eruptions, fixed drug eruptions, urticaria/ angioedema) to antibiotics, antihypertensives, cholesterol lowering agents, etc.
• Radiation therapy, chemotherapy

Adjunctive Treatment

• See management for Dry Skin above.
• Consider allergy testing to determine sensitivity.

Lifestyle Measures

• Decrease alcohol intake.
• Reduce stress.
• Avoid irritants, e.g., no harsh fabrics, harsh soaps, solvents, chlorine.
• Rinse detergents from clothing.
• Use bath oil or baking soda.
• Apply moisturizer regularly after washing.
• Refresh with cool water compresses or cooled moisturizers

Topical Agents

• Menthol 1% and/or camphor 1/4%-1/2% in aqueous cream (keep refrigerated)
• Combination products with menthol, colloidal oatmeal and shea butter (compounding not necessary).

Systemic Agents

• Antihistamine

Photosensitivity

Dermatological Causes

• Polymorphous light eruption
• Actinic prurigo
• Solar urticaria
• Brachioradial pruritus

Systemic Causes

• Systemic Lupus Erythematosus
• Porphyrias
• HIV

Therapeutic Causes

• Doxycycline, minocycline, tetracycline
• NSAIDs
• Trimethoprim-sulfamethoxazole
• Thaizide diuretics
• ACE inhibitors
• Antimalarials
• Coal tar and its derivatives
• Chlorpromazine
• Procainamide
• Vitamin A acid derivatives (e.g., isotretinoin [Accutane^®], topical retinoic acid [Retin-A®])
• Skin depigmenting agents (e.g., hydroquinone, kojic acid)

Adjunctive Treatment

• Sun avoidance
• Protective clothing
• Barrier protection with minimum SPF 30 broad spectrum sunscreens
• Antihistamines q.h.s.

Psoriasis

Systemic Causes

• Post streptococcal infection Therapeutic Causes
• Beta blockers
• Lithium
• Corticosteroid rebound phenomenon
• Antimalarials
• Interferon
• NSAIDs Adjunctive Treatment
• Moisturizers
• Antihistamines
• Sunburn avoidance
• Avoidance of drugs that exacerbate the condition

Scaly Scalp

Dermatological Causes

• Psoriasis
• Seborrheic dermatitis
• Dandruff

Adjunctive Treatment

• Salicylic acid 1%-4% +/- olive oil (never use if patient has seborrheic dermatitis as it promotes growth of causative yeast), mineral oil
• Shampoos containing selenium sulphide, zinc pyrithione, tar
• Tar (e.g., 10%-20% coal tar solution; liquor carbonis detergent in a topical steroid ointment)

Pimples/Acne

Dermatological Causes

• Acne vulgaris

Systemic Causes

• Hyperandrogen states (e.g., polycystic ovarian syndrome)
• Menstruation hormonal factors
• NB: foods are not an aggravating factor

Therapeutic Causes

• Cosmetic products containing lipids and cocoa butter
• Heavy oils, greases, and tars
• Topical drugs containing tars, ointments, and corticosteroids
• Corticosteroids
• Androgens
• Halogens (e.g., systemic dioxin poisoning causing chloracne)
• Lithium
• Antituberculosis drugs (e.g., isoniazid)
• Antiepileptics (e.g., carbamazepine, phenytoin)
• Some formulations of oral contraceptives

Adjunctive Treatment

• Daily facial washes and cleansers specially formulated for oily skin
• Low dose benzoyl peroxide washes
• Non-comedogenic moisturizing lotion

For patients taking systemic retinoids (e.g., isotretinoin):

• Eyes: saline drops
• Nose: petroleum jelly ointment
• Lips: lip balm
• Dry skin: daily moisturizers

Rosacea

Therapeutic Causes

• Niacin

Adjunctive Treatment

• Avoid aggravating factors that induce flushing/ telangiectasia development: spicy food, alcohol, hot drinks, and heat-inducing activities.
• Warn patients not to apply potent topical corticosteroids to the face.
• Medical therapies help to resolve pustulation, papulation, and erythema, but have a minimal effect on the suppression of flushing and established telangiectasia.
• Some laser therapies can be effective.
• Cosmetic camouflage (e.g., Cover FX^®) may be especially helpful for females.
• Methylsulfonylmethane + silymarin (Rosacure^®) helps minimize appearance of erythema.

Clinical Pearls

Patient Education

Providing patient education along with adjunctive therapies can help reduce frustration and improve patient compliance.

• Use simple skin care regimen, e.g., mild washes and daily facial moisturizer.

Sunscreen

• Apply broad spectrum, photostable formulation with SPF
• 30 before going out in the sun.
• Reapply frequently.
• A fairly thick application is needed for effectiveness.

Tar and its derivatives

• Stains fabrics yellow.
• Apply at night along the grain of hair growth to avoid folliculitis.
• Use old sheets to reduce concern about staining.
• Turns white hair a straw color.
• Patients with white hair should be warned to use on scalp with caution.

Benzoyl peroxide

• Bleaches fabrics. To minimize:
• Use a white towel to dry face after use.
• Avoid contact with fabrics until skin is dry.
• Use at night to avoid bleaching good clothing.

Antihistamines

• Caution patient regarding drowsiness and consider recommending non-drowsy antihistamine (e.g., cetirizine [ReactineR], desloratadine [AeriusR] during the day).

Conclusion

Pharmacists can play a key role in helping patients with skin concerns by recognizing causes of common skin symptoms and
recommending therapy to patients. They can counsel patients on behavioral strategies to help reduce disease severity and recurrence,
and help patients choose products well-matched for a given skin condition. When counseling patients, a reactive approach to their
concerns is appropriate, but a proactive approach is superior as this provides the best possible care.

Hyperpigmentation

• Hyperpigmentation is very common and results from excess cutaneous melanin deposition causing a color change:
  • Epidermal involvement appears as brown discoloration.
  • Dermal deposition is blue-grey.
  • Mixed epidermal-dermal depositions are brown-grey.
• Melanin can be deposited in the epidermis or dermis; dermal hyperpigmentation is much more challenging to treat.
• A Wood’s lamp is beneficial for determining the location of melanin deposition.
  • Shows enhancement of color contrast in epidermal lesions, but not dermal lesions. The mixed type has enhancement in some areas of lesional skin, but not in others.
• The most common pigmentation disorders for which patients seek treatment are melasma and postinflammatory hyperpigmentation (PIH).
• Multiple topical modalities can be used, and combination topical therapies are the current first-line approach.

Melasma

• Occurs mainly in women of all racial and ethnic groups, particularly those with Fitzpatrick skin types IV to VI:
  • Type IV (olive) – Rarely burns, always tans
  • Type V (brown) – Very rarely burns, always tans
  • Type VI (black) – Never burns, always tans
• There are multiple factors involved including:
  • A genetic predisposition
  • Ultraviolet light exposure
  • Estrogen exposure, thought to induce melasma
  • During pregnancy, which clears within a few months of delivery.
  • With use of oral contraceptives and hormone replacement therapy in postmenopausal women. However, discontinuation of these drugs rarely clears this condition.
• Presents as brown to grey macules and patches, with serrated, irregular, and geographic borders. The pigmented patches are usually sharply demarcated and symmetrical.
• Melasma has a predilection for sun exposed areas.
• The three major patterns of distribution are:
  • Centrofacial (cheeks, forehead, upper lip, nose, and chin)
  • Malar (cheeks and nose)
  • Mandibular (rami of mandible).

Postinflammatory Hyperpigmentation (PIH)

• • Represents a pathophysiologic response to cutaneous inflammation, e.g., acne, atopic dermatitis, lichen planus, and psoriasis.

• More obvious in patients with brown or black skin with no gender or age predominance.
• Lesions characteristically limited to the site of the preceding inflammation and have indistinct, feathered borders.
• Epidermal hyperpigmentation (e.g., associated with acne) occurs when increased melanin is transferred to keratinocytes.
• Dermal pigmentation (e.g., associated with lichen planus and cutaneous lupus erythematosus) occurs when the basement membrane is disrupted and melanin falls into the dermis and resides within melanophages.
• Initial treatments for PIH should involve an attempt at treating the underlying skin condition.

Hyperpigmentation Treatments

• Therapeutic goals include
• Inhibiting the formation of melanosomes
• Promoting the degradation of melanosomes
• Retarding the proliferation of melanocytes.
• Sun exposure is an important etiologic factor, therefore all patients should use daily, broad-spectrum, 15 SPF-minimum sunscreens and minimize sun exposure.
• The same treatment principles hold for PIH and melasma.
• Treatment of melasma in pregnant women is routinely deferred until after delivery.

Hydroquinone (HQ) 2%-4%

• Widely used for melasma therapy.
• Patch testing elsewhere on the body, e.g., the upper inner arm, should be done to confirm nonallergenicity prior to attempting a trial of bleaching agents.
• Side-effects include irritant and allergic contact dermatitis, PIH, nail bleaching, and rarely, ochronosis-like pigment.
• Under no circumstances should monobenzylether of hydroquinone or other ethers of HQ be used to treat melasma as they can lead to a permanent loss of melanocytes with the development of a disfiguring confetti-like leukoderma.
• HQ regulatory safety issues may pose availability issues.

Retinoids

• Tretinoin (0.05%-0.1%) reduces pigmentation by inhibiting tyrosinase transcription, and interrupting melanin synthesis.
• Typically takes at least 24 weeks to see clinical improvement.
• May increase pigmentation secondary to irritation.
• May cause erythema and peeling.
• Other retinoids including adapalene, tazarotene and topical isotretinoin have also been used.

Azelaic Acid (15%-20%)

• A reversible inhibitor of tyrosinase.
• May have cytotoxic and antiproliferative effects on melanocytes.
• Was shown to be as effective as HQ 4% without HQ’s side effects.[Balina LM, et al. Int J Dermatol 30:893-5 (1991).]
• Adverse effects include pruritus, mild erythema, scaling, and burning.

Kojic Acid (2%)

• Produced by the fungus Aspergilline oryzae and is a tyrosinase inhibitor.
• Generally equivalent to other therapies but may be more irritating.
• May be effective if a patient has difficulty tolerating other first-line therapies.[Cayce KA, et al. Derm Nursing 16(5):401-6, 413-6 (2004).]

Glycolic Acid (5%-10%)

• An alpha-hydroxy acid
• Reduces pigment by
  • thinning the stratum corneum.
  • enhancing epidermolysis.
  • dispersing melanin in the basal layer of the epidermis.
  • increasing collagen synthesis in the dermis.

Combination Therapy

• Combination therapy is more effective than single agents used alone.
• Kligman formula (HQ 5%, tretinoin 0.1% and dexamethasone 0.1%) is the most widely used combination therapy for melasma worldwide.[Kligman AM, et al. Arch Dermatol 111:40-8 (1975).]
• The combination of azelaic acid with 0.05% tretinoin or 15-20% glycolic acid may produce earlier, more pronounced lightening.[Finlay AY. Br J Dermatol 136:305-14 (1997).]
• Kojic acid 2% combined with HQ 2% was shown to be superior to glycolic acid 10% and HQ 2%.[Lim JT. Dermatol Surg 25:282-4 (1999).]
• • Glycolic acid 5% with either HQ 4% or kojic acid 4% for 3 months proved equally effective with reduction of pigmentation in 51% of patients.[Garcia A, et al. Dermatol Surg 22:443-7 (1996).]
• • Glycolic acid 10% plus HQ 4% in a cream of vitamins C and E and sunscreen was effective in 75% of patients.[Guevara IL, et al. Int J Dermatol 43:966-72 (2003).]
• • A new combination of HQ 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (Tri-Luma^®) proved effective with 77% of patients showing complete or nearly complete clearing in this multi-centre, randomized, double-blind, control trial.[Taylor SC, et al. Cutis 72:67-72 (2003).]

Over-the-Counter Medications

• Are readily available.
• HQ for OTC use not as effective as stronger prescription formulations.[Halder R, et al. Skin Therapy Lett 9(6):1-3 (2004 Jun-Jul).]
• Alpha and beta hydroxy acid home chemical peels and topical vitamin A are also available.
• New formulation: 2% N-acetyl glucosamine (NAG) and 4% niacinamide (Olay^® Definity^®)
• Recently shown to reduce facial hyperpigmentation in Japanese and Caucasian subjects with facial hyperpigmentation in two double-blind, vehicle-controlled, split-face, left-right randomized clinical studies.[Bissett D, et al. Topical Nacetyl glucosamine reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster#236.]
• In another double-blind, vehicle controlled, full-face, clinical study, a significant reduction in facial hyperpigmented spots was seen in patients with facial hyperpigmentation using the NAG 2% + niacinamide 4% formulation when compared with the vehicle regimen.[Kimball AB, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster #235.]
• There were no adverse effects reported in any of the studies.
• Improvement seen in 4-8 weeks.

Miscellaneous Treatments

Other topical therapies have been used including ascorbic acid, licorice extract, and in the past, mercury.[Rendon M, et al. J Am Acad Dermatol 54(5 Suppl):S272-81 (2006).]

*This article was adapted from Lynde CB, Kraft JN, Lynde CW. Melasma and postinflammatory hyperpigmentation and their treatments. Skin Therapy Lett 11(9):1-4 (2006 Nov).

Faculty of Medicine, University of Toronto, Toronto, Canada

ABSTRACT

Hyperpigmentation disorders of the skin are common and can be the source of significant psychosocial distress for patients. The most common of these disorders are melasma and postinflammatory hyperpigmentation. Sunscreen use and minimizing sun exposure are crucial in all cases. Topical applications are the mainstay of treatment and include phenols, retinoids, corticosteroids, and their combinations.

Key Words:
hyperpigmentation, melasma, postinflammatory hyperpigmentation, PIH

Hyperpigmentation of the skin is a very common problem, with many patients seeking therapies to improve their cosmetic appearance. It is the result of an increase in cutaneous melanin deposition either by increased melanin synthesis or, less commonly, by a greater number of melanocytes. The amount of color change depends on the location of the melanin deposition. Epidermal involvement appears as brown discoloration whereas dermal deposition appears as blue-grey.¹ Mixed epidermal and dermal depositions appear as brown-grey discolorations. The use of a Wood’s lamp can often be very beneficial in determining the location of melanin deposition showing enhancement of color contrast in lesional skin for the epidermal type, but not the dermal types. The mixed type has enhancement in some areas of lesional skin, but not in other areas.² Whether the melanin is deposited in the epidermis or dermis is important therapeutically because dermal hyperpigmentation is much more challenging to treat.³

The most common pigmentation disorders for which patients seek treatment are melasma and postinflammatory hyperpigmentation (PIH). These conditions may have a major impact because disfiguring facial lesions can significantly affect a person’s psychological and social wellbeing, contributing to lower productivity, social functioning, and self-esteem.^4,5

Melasma

Melasma is a common acquired pigmentary disorder that occurs mainly in women (more than 90% of cases)⁶ of all racial and ethnic groups, but particularly affects those with Fitzpatrick skin types IV–VI.⁷ While the cause of melasma is unknown, factors include: a genetic predisposition, ultraviolet light exposure, and estrogen exposure.⁸ Estrogen is thought to induce melasma as it often develops during pregnancy, with use of oral contraceptives, and with hormone replacement therapy (HRT) in postmenopausal women.9 Melasma in pregnancy usually clears within a few months of delivery.

Discontinuation of oral contraceptives or HRT, in combination with adequate sun protection, may also result in melasma clearance,¹⁰ although there is a paucity of literature with regard to HRT and the clearance of this condition.

Melasma presents as brown to grey macules and patches, with serrated, irregular, and geographic borders.⁷ The pigmented patches are usually sharply demarcated¹⁰ and symmetrical. Melasma has a predilection for sun-exposed areas. The three major patterns of distribution are: centrofacial (cheeks, forehead, upper lip, nose, and chin) (66% of cases), malar (cheeks and nose) (20% of cases) and mandibular (rami of the mandible) (15% of cases). See Table 1 for the differential diagnosis.⁸

Postinflammatory Hyperpigmentation (PIH)

PIH represents a pathophysiologic response to cutaneous inflammation, such as acne, atopic dermatitis, lichen planus, and psoriasis. Similar to melasma, it is more obvious in patients with brown or black skin.⁸ It has no gender or age predominance.¹⁰ The lesions are characteristically limited to the site of the preceding inflammation and have indistinct, feathered borders.⁷ Melanocytes can either be stimulated by the inflammatory process to become hypertrophic, thus secreting more melanin, or the number of melanocytes can increase. Epidermal hyperpigmentation (e.g., associated with acne) occurs when increased melanin is transferred to keratinocytes while dermal pigmentation (e.g., associated with lichen planus and cutaneous lupus erythematosus) occurs when the basement membrane is disrupted and melanin falls into the dermis and resides within melanophages.⁸

Any inflammatory disorder can be associated with PIH, including:

• Acne vulgaris
• Atopic dermatitis
• Discoid lupus erythematosus
• Erythema dyschromicum perstans
• Fixed drug eruption
• Generalized drug eruption
• Idiopathic eruptive macular pigmentation
• Impetigo
• Insect bites
• Irritant and allergic contact and photocontact-
• dermatitis
• Lichen planus
• Lichen simplex chronicus
• Morphea
• Pityriasis rosea
• Polymorphous light eruption
• Psoriasis
• Trauma (i.e., burns, abrasions, postsurgical)
• Viral exanthem

Hyperpigmentation Treatments

Therapeutic goals for hyperpigmentation include promoting the degradation of melanosomes, inhibiting the formation of melanosomes, and retarding the proliferation of melanocytes.11 Because sun exposure is an important etiologic factor in hyperpigmentation, all patients should use daily, broad-spectrum, high SPF sunscreens and minimize sun exposure.12 Although this practice is widely used there are no clinical trials to support its therapeutic benefit. Most of the therapies used for hyperpigmentation have been studied in melasma and the same treatment principles hold for PIH.³

Topical Treatments for Melasma

In those patients with epidermal type melasma, there are multiple treatments available (see Table 2).6 Topical agents include phenols, e.g., hydroquinone (HQ); retinoids, e.g., tretinoin; azelaic acid; kojic acid (KA); and glycolic acid (GA).

Hydroquinone

HQ 2%–4% has been widely used for melasma therapy. It inhibits the conversion of dopa to melanin by inhibiting the activity of tyrosinase.¹³ Moreover, Jimbow, et al. proposed that it may interfere with DNA and RNA synthesis, degrade melanosomes, and destroy melanocytes.¹⁴

There are rare case reports of allergic contact dermatitis to HQ,15-17 however, irritant reactions are more common, with up to 25% developing an itchy eruption as demonstrated in a recent randomized control trial.18 We recommend that patients test HQ on a hidden area, e.g., the upper inner arm, prior to use on areas that are especially visible, such as the face.

Ennes, et al. compared HQ 4% with placebo over 12 weeks in 48 patients who had melasma. Thirty-eight percent of HQ patients showed total improvement and 57% demonstrated partial improvement. Only 8% of placebo patients achieved total improvement and 17% were treatment failures.¹⁹ Side-effects included irritant and allergic contact dermatitis, PIH, nail bleaching and rarely, ochronosis-like pigmentation.⁸ Toxicity studies have shown HQ is capable of inducing renal adenoma in rats and is fetotoxic in animals.²⁰ These findings influenced the EU to ban HQ agents as a cosmetic. However, these complications have not been reported in humans.²¹

Under no circumstances should monobenzylether, or any other ethers of HQ, be used to treat melasma as they can lead to a permanent loss of melanocytes with the development of a disfiguring confetti-like leukoderma.⁷

Retinoids

Tretinoin 0.05%–0.1% reduces pigmentation by inhibiting tyrosinase transcription, as well as by interrupting melanin synthesis.²² While tretinoin may be effective in reducing melasma, it typically takes at least 24 weeks to see clinical improvement.²³ It may also increase pigmentation secondary to irritation10 and may cause erythema and peeling.24 Other retinoids including adapalene, tazarotene and topical isotretinoin have also been used.^25,26

Azelaic Acid

Azelaic acid (15%–20%) (Finacea^®, Intendis), a C9 dicarboxylic acid, is a reversible inhibitor of tyrosinase27 and may also have both cytotoxic and antiproliferative effects on melanocytes.²⁸ In a randomized, double-blind study, azelaic acid was shown to be as effective as HQ 4% but without its side effects.²⁹ The combination of azelaic acid with 0.05% tretinoin or 15%–20% glycolic acid may produce earlier, more pronounced skin lightening.⁸ Adverse effects include pruritus, mild erythema, scaling, and burning.²⁸

Kojic Acid

KA 2% is produced by the fungus Aspergilline oryzae and is a tyrosinase inhibitor.⁷ It is generally equivalent to other therapies but may be more irritating.30 In one double-blind study, KA 2% combined with HQ 2% was shown to be superior to glycolic acid (GA) 10% and HQ 2%.31 Another double-blind study compared GA 5% with either HQ 4% or KA 4% for 3 months. Both combinations proved equally effective with reduction of pigmentation in 51% of patients.³² KA may be effective if a patient has difficulty tolerating other first-line therapies.³⁰

Glycolic Acid

GA 5%–10% is an alpha-hydroxy acid and has been studied in combination with other agents. It decreases pigment by many mechanisms including thinning the stratum corneum, enhancing epidermolysis, dispersing melanin in the basal layer of the epidermis, and increasing collagen synthesis in the dermis.² One combination study compared GA 10% plus HQ 4% in a cream that included vitamins C and E and sunscreen vs. sunscreen cream alone. Seventy-five percent of patients improved using the treatment enhanced cream compared with only 13% who used the sunscreen alone. Mild irritation was a common adverse effect.³³

Combination Therapy

Combination therapy is more effective than single agents used alone. The etiology of melasma is not completely understood, thus, therapies that can act at different stages of pigmentation can produce better clinical results than a single therapy acting at a single stage.⁶

The addition of tretinoin eliminates pigment and increases keratinocyte proliferation by preventing the oxidation of HQ and improving epidermal penetration. Further, adding topical corticosteroids reduces the irritative effects of hypopigmenting agents, and inhibits melanin synthesis by decreasing cellular metabolism.⁶ This combination, HQ 5%, tretinoin 0.1%, and dexamethasone 0.1%, was first introduced in 1975 and termed the Kligman formula after its inventor. It has been the most extensively used combination therapy for melasma worldwide.³⁴

More recently, results from a multicenter, randomized, double-blind control trial demonstrated that a new combination of HQ 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (Tri-Luma^®, Galderma) proved better than any combination of two of the above agents, with 77% of patients showing complete or nearly complete clearing. Clinically significant improvement was noted as early as 4 weeks with maximum results at 8 weeks. The most common adverse effects were mild local irritation, erythema, and skin peeling.35 The mixture should be applied to the entire affected area to avoid blotchiness. The recent 2006 consensus of the Pigmentary Disorders Academy (PDA), a group of international dermatologists and leaders in pigmentary disorders who receive sponsorship from Galderma, supported the use of triple therapy.

The PDA consensus suggested that first-line therapy for melasma should consist of fixed topical therapies and only when triple combination therapy is unavailable or patients have a sensitivity to the ingredients, should dual ingredients or single agents be considered.⁶

Over-the-Counter Products

Over-the-counter (OTC) products are readily available, and many patients have already tried these measures prior to consulting a dermatologist. At the present time the available concentrations of HQ for OTC use are not as efficacious as prescription formulations.³⁶ Alpha and beta hydroxy acid home chemical peels and topical vitamin A are also available.

The combination of N-acetyl glucosamine (NAG) and niacinamide (Olay^® Definity^®) was recently shown to reduce facial hyperpigmentation in Japanese and Caucasian subjects with facial hyperpigmentation in two double-blind, vehicle-controlled, split-face, left-right randomized clinical studies.³⁷ In another double-blind, vehicle-controlled, full-face clinical study, a significant reduction in facial hyperpigmented spots was seen in patients with facial hyperpigmentation using the NAG 2% + niacinamide 4% formulation when compared with the vehicle regimen.³⁸ There were no adverse effects reported.

Miscellaneous Treatments

Other topical therapies have been used including ascorbic acid, licorice extract and, in the past, mercury.⁶

Treatment During Pregnancy

Treatment of melasma in pregnant women is routinely deferred until after delivery. This is because, first of all, melasma is more resistant to treatment because the hormonal trigger for it persists throughout pregnancy.³⁹ Second, therapy may be unnecessary since most women have a significant improvement in melasma after parturition. Third, therapy for melasma is contraindicated during pregnancy.

Treatment of PIH

Initial treatments for PIH should, if possible, manage and control the underlying skin condition.¹⁰ To lower the risk of PIH in patients with inflammatory conditions such as acne and atopic dermatitis, they should present early to a physician. As with melasma, sunscreen and sun avoidance are extremely important. Other treatment options are similar to those discussed above for melasma.² A clinical trial evaluated the effects of 0.1% tretinoin cream on PIH in patients with Type VI skin. Although significant lightening effects were seen, 50% of patients in the treatment group experienced moderate dermatitis.⁴⁰

Another PIH treatment study observed the addition of GA peels to a topical regimen of HQ 2%, GA 10% and tretinoin 0.05% cream in PIH patients with Type VI skin. This study showed improvement with peels and minimal adverse effects.41 However, as mentioned earlier, caution must be taken when performing peels on darker skinned patients because there is a higher risk of hyperpigmentation.³⁰

Conclusion

Hyperpigmentation, most commonly melasma and PIH, remain a therapeutic challenge. Multiple topical modalities can be used, and combination topical therapies are the current first-line approach.

References

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41. Burns RL, Prevost-Blank PL, Lawry MA, Lawry TB, Faria DT, Fivenson DP. Glycolic acid peels for postinflammatory hyperpigmentation in black patients. A comparative study. Dermatol Surg 23(3):171-4 (1997 Mar).