Hydroquinone: Complications and Controversies

With photographs of a much lighter-skinned Sammy Sosa in the media recently, questions about bleaching agents and their effects have been posed by our patients and by the media.

Skin-lightening agents are essential products for hyperpigmentation, particularly in persons of color, for whom the stigma of common skin disorders such as acne is magnified by the post-inflammatory hyperpigmentation these conditions leave as their mark. Although there are numerous skin-lightening agents on the market, including azelaic acid, mequinol, retinoids, glycolic acid, kojic acid, licorice, arbutin, soy, N-acetyl glucosamine, ascorbic acid, and niacinamide, hydroquinone (HQ) has been our workhorse.

In 1961, Dr. Malcolm C. Spencer evaluated the efficacy of hydroquinone 1.5% and 2% in 98 subjects with hyperpigmentation. Improvement was noted in 45% of subjects, with no reports of adverse events. Since this seminal study, HQ has been the standard for treatment of hyperpigmentation. HQ blocks the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibiting tyrosinase, a copper-containing enzyme of plant and animal tissues that catalyzes the production of melanin and other pigments. It may also inhibit RNA and DNA synthesis, degrade melanosomes, and destroy melanocytes.

Currently, HQ is commonly used in concentrations of 2% over the counter, 4% by standard prescription, or prescribed in higher concentrations or compounded with other agents (particularly retinoids or glycolic acid) to offer maximal efficacy. The Kligman formula, containing 5% HQ, 0.1% tretinoin, and 0.1% dexamethasone, and modifications of this formula, has emerged as the most popular combination. 

Side effects of HQ are both acute and chronic. Acute complications include irritant or allergic contact dermatitis and postinflammatory hyper- and hypopigmentation. Of these, irritant reactions are the most common. Review of the literature suggests that monotherapy hydroquinone agents cause irritant reactions in 0%-70% of patients. In combination therapy, the incidence rises to 10%-100%.  Reports of allergic contact sensitization to hydroquinone are infrequent.

Chronic adverse events related to exposure to hydroquinone are of greater concern. These complications include ochronosis, nail discoloration, conjunctival melanosis, and corneal degeneration. Ochronosis is the most common chronic complication related to long-term use of hydroquinone. The condition was initially described by G.H. Findlay and associates among South African Bantu women who applied high concentrations of hydroquinone (6%-8.5%) for many years (Br. J. Dermatol. 1975;93:613-22). Clinically, ochronosis is characterized by asymptomatic hyperpigmentation, erythema, papules, papulonodules, and grey-blue colloid milia on sun-exposed areas of the skin. Although ochronosis has been commonly described among women in Africa, it is uncommon in the United States despite its extensive use. There were less than 25 reported cases of hydroquinone-associated ochronosis in the United States in the past 25 years. Certainly, there may be unreported cases; however, conservative use of the data suggests that there would be one case of exogenous ochronosis for every 300-450 million units of hydroquinone sold in the United States. The majority of reported U.S. cases have occurred with 2% hydroquinone.

As Dr. Pearl Grimes stated in the Seminars of Cutaneous Medicine and Surgery: Skin of Color issue, “factors accounting for the disparity in the frequency of ochronosis in the U.S. and Africa include the routine use of sunscreens and the absence of resorcinol in formulations in the States. In addition, in contrast to Africa, there are few hydroethanolic formulations marketed in the U.S. Such formulations may permit enhanced absorption of HQ (2009;28:77-85). In addition, the Bantu women described in the original article by Findlay used higher concentrations of hydroquinone over extensive body surface areas, several times a day, for years or, in some cases, decades.

Hydroquinone has been banned in some countries, including over-the-counter dispensed formulations of 2% HQ by the European Cosmetic Product Regulation. In August 2006, the U.S. Food and Drug Administration (FDA) proposed a ban on OTC HQ and considered requiring new drug applications for 4% formulations due to concerns regarding ochronosis and possible carcinogenicity. Some animal studies have shown an increase in cancers that are species and sex specific, but there are no human studies documenting an increased incidence of skin cancer or internal malignancies in users of HQ.

Details on the FDA’s proposed ban are as follows: on Aug. 29, 2006, the FDA published a monograph in the U.S. Federal Register proposing that all hydroquinone products, which have not been approved through the new drug application process, be considered misbranded and therefore banned. This so-called “proposed rule” allowed anyone to submit comments to the FDA by a specified date (in this case Dec. 27, 2006 – later extended 30 days) before the so-called “final rule” would be published. Once the final rule is published in the Federal Register, manufacturers would have 30 days to remove noncompliant hydroquinone products from the marketplace or risk seizure, fines, and possibly imprisonment. Now, in 2010, the verdict on the proposed FDA ban is still pending.

Though controversial, hydroquinone still remains the workhorse of dermatologists for the treatment of melasma and postinflammatory hyperpigmentation. Until a safe, more widely accepted, and efficacious product is developed, we will continue the search to find the best treatment for skin of color patients.

With photographs of a much lighter-skinned Sammy Sosa in the media recently, questions about bleaching agents and their effects have been posed by our patients and by the media.

Skin-lightening agents are essential products for hyperpigmentation, particularly in persons of color, for whom the stigma of common skin disorders such as acne is magnified by the post-inflammatory hyperpigmentation these conditions leave as their mark. Although there are numerous skin-lightening agents on the market, including azelaic acid, mequinol, retinoids, glycolic acid, kojic acid, licorice, arbutin, soy, N-acetyl glucosamine, ascorbic acid, and niacinamide, hydroquinone (HQ) has been our workhorse.

In 1961, Dr. Malcolm C. Spencer evaluated the efficacy of hydroquinone 1.5% and 2% in 98 subjects with hyperpigmentation. Improvement was noted in 45% of subjects, with no reports of adverse events. Since this seminal study, HQ has been the standard for treatment of hyperpigmentation. HQ blocks the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibiting tyrosinase, a copper-containing enzyme of plant and animal tissues that catalyzes the production of melanin and other pigments. It may also inhibit RNA and DNA synthesis, degrade melanosomes, and destroy melanocytes.

Currently, HQ is commonly used in concentrations of 2% over the counter, 4% by standard prescription, or prescribed in higher concentrations or compounded with other agents (particularly retinoids or glycolic acid) to offer maximal efficacy. The Kligman formula, containing 5% HQ, 0.1% tretinoin, and 0.1% dexamethasone, and modifications of this formula, has emerged as the most popular combination. 

Side effects of HQ are both acute and chronic. Acute complications include irritant or allergic contact dermatitis and postinflammatory hyper- and hypopigmentation. Of these, irritant reactions are the most common. Review of the literature suggests that monotherapy hydroquinone agents cause irritant reactions in 0%-70% of patients. In combination therapy, the incidence rises to 10%-100%.  Reports of allergic contact sensitization to hydroquinone are infrequent.

Chronic adverse events related to exposure to hydroquinone are of greater concern. These complications include ochronosis, nail discoloration, conjunctival melanosis, and corneal degeneration. Ochronosis is the most common chronic complication related to long-term use of hydroquinone. The condition was initially described by G.H. Findlay and associates among South African Bantu women who applied high concentrations of hydroquinone (6%-8.5%) for many years (Br. J. Dermatol. 1975;93:613-22). Clinically, ochronosis is characterized by asymptomatic hyperpigmentation, erythema, papules, papulonodules, and grey-blue colloid milia on sun-exposed areas of the skin. Although ochronosis has been commonly described among women in Africa, it is uncommon in the United States despite its extensive use. There were less than 25 reported cases of hydroquinone-associated ochronosis in the United States in the past 25 years. Certainly, there may be unreported cases; however, conservative use of the data suggests that there would be one case of exogenous ochronosis for every 300-450 million units of hydroquinone sold in the United States. The majority of reported U.S. cases have occurred with 2% hydroquinone.

As Dr. Pearl Grimes stated in the Seminars of Cutaneous Medicine and Surgery: Skin of Color issue, “factors accounting for the disparity in the frequency of ochronosis in the U.S. and Africa include the routine use of sunscreens and the absence of resorcinol in formulations in the States. In addition, in contrast to Africa, there are few hydroethanolic formulations marketed in the U.S. Such formulations may permit enhanced absorption of HQ (2009;28:77-85). In addition, the Bantu women described in the original article by Findlay used higher concentrations of hydroquinone over extensive body surface areas, several times a day, for years or, in some cases, decades.

Hydroquinone has been banned in some countries, including over-the-counter dispensed formulations of 2% HQ by the European Cosmetic Product Regulation. In August 2006, the U.S. Food and Drug Administration (FDA) proposed a ban on OTC HQ and considered requiring new drug applications for 4% formulations due to concerns regarding ochronosis and possible carcinogenicity. Some animal studies have shown an increase in cancers that are species and sex specific, but there are no human studies documenting an increased incidence of skin cancer or internal malignancies in users of HQ.

Details on the FDA’s proposed ban are as follows: on Aug. 29, 2006, the FDA published a monograph in the U.S. Federal Register proposing that all hydroquinone products, which have not been approved through the new drug application process, be considered misbranded and therefore banned. This so-called “proposed rule” allowed anyone to submit comments to the FDA by a specified date (in this case Dec. 27, 2006 – later extended 30 days) before the so-called “final rule” would be published. Once the final rule is published in the Federal Register, manufacturers would have 30 days to remove noncompliant hydroquinone products from the marketplace or risk seizure, fines, and possibly imprisonment. Now, in 2010, the verdict on the proposed FDA ban is still pending.

Though controversial, hydroquinone still remains the workhorse of dermatologists for the treatment of melasma and postinflammatory hyperpigmentation. Until a safe, more widely accepted, and efficacious product is developed, we will continue the search to find the best treatment for skin of color patients.

With photographs of a much lighter-skinned Sammy Sosa in the media recently, questions about bleaching agents and their effects have been posed by our patients and by the media.

Skin-lightening agents are essential products for hyperpigmentation, particularly in persons of color, for whom the stigma of common skin disorders such as acne is magnified by the post-inflammatory hyperpigmentation these conditions leave as their mark. Although there are numerous skin-lightening agents on the market, including azelaic acid, mequinol, retinoids, glycolic acid, kojic acid, licorice, arbutin, soy, N-acetyl glucosamine, ascorbic acid, and niacinamide, hydroquinone (HQ) has been our workhorse.

In 1961, Dr. Malcolm C. Spencer evaluated the efficacy of hydroquinone 1.5% and 2% in 98 subjects with hyperpigmentation. Improvement was noted in 45% of subjects, with no reports of adverse events. Since this seminal study, HQ has been the standard for treatment of hyperpigmentation. HQ blocks the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibiting tyrosinase, a copper-containing enzyme of plant and animal tissues that catalyzes the production of melanin and other pigments. It may also inhibit RNA and DNA synthesis, degrade melanosomes, and destroy melanocytes.

Currently, HQ is commonly used in concentrations of 2% over the counter, 4% by standard prescription, or prescribed in higher concentrations or compounded with other agents (particularly retinoids or glycolic acid) to offer maximal efficacy. The Kligman formula, containing 5% HQ, 0.1% tretinoin, and 0.1% dexamethasone, and modifications of this formula, has emerged as the most popular combination. 

Side effects of HQ are both acute and chronic. Acute complications include irritant or allergic contact dermatitis and postinflammatory hyper- and hypopigmentation. Of these, irritant reactions are the most common. Review of the literature suggests that monotherapy hydroquinone agents cause irritant reactions in 0%-70% of patients. In combination therapy, the incidence rises to 10%-100%.  Reports of allergic contact sensitization to hydroquinone are infrequent.

Chronic adverse events related to exposure to hydroquinone are of greater concern. These complications include ochronosis, nail discoloration, conjunctival melanosis, and corneal degeneration. Ochronosis is the most common chronic complication related to long-term use of hydroquinone. The condition was initially described by G.H. Findlay and associates among South African Bantu women who applied high concentrations of hydroquinone (6%-8.5%) for many years (Br. J. Dermatol. 1975;93:613-22). Clinically, ochronosis is characterized by asymptomatic hyperpigmentation, erythema, papules, papulonodules, and grey-blue colloid milia on sun-exposed areas of the skin. Although ochronosis has been commonly described among women in Africa, it is uncommon in the United States despite its extensive use. There were less than 25 reported cases of hydroquinone-associated ochronosis in the United States in the past 25 years. Certainly, there may be unreported cases; however, conservative use of the data suggests that there would be one case of exogenous ochronosis for every 300-450 million units of hydroquinone sold in the United States. The majority of reported U.S. cases have occurred with 2% hydroquinone.

As Dr. Pearl Grimes stated in the Seminars of Cutaneous Medicine and Surgery: Skin of Color issue, “factors accounting for the disparity in the frequency of ochronosis in the U.S. and Africa include the routine use of sunscreens and the absence of resorcinol in formulations in the States. In addition, in contrast to Africa, there are few hydroethanolic formulations marketed in the U.S. Such formulations may permit enhanced absorption of HQ (2009;28:77-85). In addition, the Bantu women described in the original article by Findlay used higher concentrations of hydroquinone over extensive body surface areas, several times a day, for years or, in some cases, decades.

Hydroquinone has been banned in some countries, including over-the-counter dispensed formulations of 2% HQ by the European Cosmetic Product Regulation. In August 2006, the U.S. Food and Drug Administration (FDA) proposed a ban on OTC HQ and considered requiring new drug applications for 4% formulations due to concerns regarding ochronosis and possible carcinogenicity. Some animal studies have shown an increase in cancers that are species and sex specific, but there are no human studies documenting an increased incidence of skin cancer or internal malignancies in users of HQ.

Details on the FDA’s proposed ban are as follows: on Aug. 29, 2006, the FDA published a monograph in the U.S. Federal Register proposing that all hydroquinone products, which have not been approved through the new drug application process, be considered misbranded and therefore banned. This so-called “proposed rule” allowed anyone to submit comments to the FDA by a specified date (in this case Dec. 27, 2006 – later extended 30 days) before the so-called “final rule” would be published. Once the final rule is published in the Federal Register, manufacturers would have 30 days to remove noncompliant hydroquinone products from the marketplace or risk seizure, fines, and possibly imprisonment. Now, in 2010, the verdict on the proposed FDA ban is still pending.

Though controversial, hydroquinone still remains the workhorse of dermatologists for the treatment of melasma and postinflammatory hyperpigmentation. Until a safe, more widely accepted, and efficacious product is developed, we will continue the search to find the best treatment for skin of color patients.