Overview:
Hydroquinone (HQ) is benzene-1,4-diol, a derivative of phenol that is further metabolized to glutathione. Hydroquinone and its derivative, arbutin, are commonly used as a topical treatment for skin hyperpigmentation. Hydroquinone cream is the standard treatment for depigmentation or skin lightening, areas of dyschromia, melasma, chloasma, solar lentigines, freckles, and post-inflammatory hyperpigmentation.
What Are the Indications for the Use of HQ?
Hydroquinone cream is the standard choice for depigmentation or skin-lightening agent. Clinically, it is used to treat dyschromia areas in the following conditions:
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Chloasma.
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Solar lentigines.
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Freckles.
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Post-inflammatory hyperpigmentation and melasma.
Post-inflammatory Hyperpigmentation:
Post-inflammatory hyperpigmentation occurs because of cutaneous inflammation, increasing melanin production. The most common causes of postinflammatory hyperpigmentation are acne vulgaris, eczematous dermatoses, contact dermatitis, psoriasis, lichen planus, and burns. Photodamage from sunlight exposure causes photodamage, increasing melanin production. Hydroquinone is used to treat postinflammatory hyperpigmentation with photoprotection. Improvement is seen over weeks to months.
Melasma:
Melasma is an acquired condition causing hyperpigmentation and is seen on sun-exposed areas of the face, forehead, cheeks, and chin. It presents a symmetrical distribution of pigmented macules and patches. The pathogenesis of melasma is related to dark skin, ultraviolet radiation, hormones, genetics, and antiepileptic medications. Exposure to UV radiation is essential in pathogenesis as UV rays increase alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone levels, thus increasing melanocyte proliferation. At the dermal layer, stem cell fibroblasts' increased expression and tyrosine kinase receptors are present in melismatic lesions, along with increased vascular endothelial growth factor (VEGF) and reactive oxygen production after UV rays-induced dermal inflammation. Vascularization and melanocyte hyperreactivity occurs due to UV-induced inflammation causing increased melanin production and hyperpigmentation. Pregnant patients who use oral contraceptives are at risk because estrogen receptors are more expressed in melasma lesions. Estrogen releases melanocyte-stimulating hormone (MSH), followed by stimulation of tyrosinase, causing increased melanin production. Melasma is frequently seen in females as compared to males. The treatment choice is the same as postinflammatory hyperpigmentation, with photoprotection and Hydroquinone as the first line of treatment.
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Photoprotection is essential in obtaining maximum benefit from Hydroquinone use. In addition, melanocytes are stimulated by ultraviolet (UVB and UVA), and visible light, causing pigmentation. Hence, it is recommended to use broad-spectrum sunscreens.
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Hydroquinone is not an FDA-approved drug due to its unknown safety. It is even banned in the European Union, Australia, and Japan.
Maintenance Treatment:
A maintenance regimen comprises triple-combination cream (TCC), 4 % Hydroquinone, Tretinoin 0.05 %, and Fluocinolone acetonide 0.01 %, applied twice weekly for 12 weeks.
A randomized controlled trial found after melasma resolution, TCC maintenance therapy with the same treatment for six months on a tapering regimen starting with three times weekly for the first month, twice weekly for the second month, followed by once weekly for the fourth month. This therapy can prevent relapse in 50 % of patients. In a study, patients with melasma were given the same TCC in a 24-week study. The cream was safe for moderate to severe melasma for up to 24 weeks when used intermittently; patients did not report even mild adverse effects, like erythema, scaling, burning, or telangiectasia.
Exogenous Ochronosis:
It is an acquired condition that develops into asymptomatic, bilateral, symmetrical, speckled blue-black macules and gray – blue pigmentation on the malar areas, temples, cheeks, and neck. Hyperpigmentation develops due to competitive inhibition of homogentisic acid and the by-products forming pigments in the dermis. Treatments for EO include Retinoic, Azelaic, Kojic acids, ablative laser therapies, and picosecond lasers. Most reports include patients using high concentrations of Hydroquinone on large areas of skin multiple times a day for years at a time. The incidence of EO is very low when topical Hydroquinone is used under guidance. Alcohol solutions predispose patients to EO. Hydroquinone is the most common cause of EO; phenol, Quinine injection, Resorcinol, and antimalarials also exacerbate it.
What Is the Mechanism of Action of HQ?
Hydroquinone acts as a skin depigmentation agent and inhibits melanin synthesis. It inhibits the conversion of L-3,4- dihydroxyphenylalanine (L-DOPA) to melanin by inhibiting tyrosinase because of its structural similarity to a melanin precursor. In healthy skin, melanocytes convert tyrosine into melanin aided by the enzyme tyrosinase. Hyperpigmentation is the consequence of the overproduction of melanin. Hydroquinone acts through reversible tyrosinase inhibition with selective melanotoxic action, thus preventing new melanin synthesis. In animal studies, Hydroquinone reduces melanosome formation, alters the internal structure of melanosomes, increases melanosome degradation, and destroys the membranous organelles in the melanocytes. The pathway of melanin synthesis is as follows:
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Hydroxylation of L-phenylalanine to L-tyrosine.
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Tyrosinase hydroxylates L-tyrosine to 3,4 L-dihydroxyphenylalanine (L-DOPA)
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L-DOPA oxidized to dopaquinone.
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Production of eumelanin and pheomelanin leads to blackish brown, yellow to reddish skin.
How to Administer HQ?
Hydroquinone is used topically to deal with pigmentation.
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A thin layer of Hydroquinone is applied and rubbed on the face and other affected areas with fingertips. This application is made one to two times daily for three to six months.
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If no results are seen after two to three months, Hydroquinone must be discontinued. It is required to apply Hydroquinone evenly on the entire face to prevent uneven pigmentation and use it with sunscreen to protect from the damaging UV light, which increases the pigmentation process.
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Physicians recommended discontinuing the treatment for a few months before starting again to decrease the risk of side effects. After that, it can be applied only during weekends or three times weekly for extended maintenance therapy with fewer complications.
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Hydroquinone is available as a two percent or four percent over-the-counter product. It is as cream, emulsion, gel, or solution.
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Multiple studies have shown maximum results using Hydroquinone as a combination therapy, retinoid, and corticosteroid. The most widely used triple combination cream comprises Hydroquinone 4 %, Tretinoin 0.05 %, and Fluocinolone acetonide 0.01 %. Use in combination with other agents needs a prescription by a dermatologist. Results are different in each patient. Around 35 % to 45 % of Hydroquinone is absorbed systemically after topical application.
What Are the Adverse Effects of HQ?
Although oral Hydroquinone is associated with cancer in animal studies, no human carcinogenicity cases have been reported. In a survey by Kandhari and Khunger, 69 patients with melasma were prescribed various combinations of Tretinoin, corticosteroids, and Hydroquinone, individual and in variety, for different durations. Erythema because of irritation by Hydroquinone, hypertrichosis, telangiectasia, acneiform eruptions, rosacea-like-eruption, epidermal atrophy, and irritant contact dermatitis were reported. Sodium metabisulfite is a preservative found in Hydroquinone formulations and can cause hives, itching, wheezing, anaphylaxis, and asthma exacerbations in susceptible individuals.
- Mutagenicity and carcinogenicity are seen as renal adenoma in genetically susceptible rats prone to chronic progressive nephropathy (CPN). Humans are not genetically predisposed to CPN, and human metabolism of HQ produces less toxic HQ conjugates than rats. HQ recommended dose does not exceed the recommended daily consumption of arbutin, a precursor of HQ in natural food like a pear with its skin, wheat germ, or coffee. The concern of HQ being leukemogenic as a benzene metabolite is not substantiated. No benzene metabolites, phenol, HQ, or benzoquinone, have the potency and level of myelotoxic effect of benzene.
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Irritation.
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Allergic contact dermatitis.
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Erythema (redness of the skin).
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Inflammation.
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Xeroderma (extremely sensitive or dry skin caused by mutations in genes).
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Stinging.
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Ochronosis that occurs as blue-black, grayish-blue discoloration; a rare condition but commonly seen in patients with a high concentration of Hydroquinone on large body surfaces for a more extended period.
Studies suggest Hydroquinone can temporarily elevate capillary glucose when measured with a glucometer. However, there is no evidence supporting that Hydroquinone cream is carcinogenic in clinical practice or human research.
What are the Contraindications for HQ?
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Allergic Reaction - Avoid taking Hydroquinone if allergic or have had hypersensitivity to Hydroquinone.
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Sun Exposure - Hydroquinone needs caution and causes photosensitivity.
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Pregnancy - Around 35 to 45 % of the topical Hydroquinone dose is absorbed systemically. Recent studies did not show a higher risk of malformations or adverse effects in pregnant women, but it is advised to minimize exposure due to absorption. In addition, the safety of breastfeeding mothers and children is unclear, so breastfeeding females should avoid using Hydroquinone.
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Monitoring - Monitoring is needed to evaluate any hypersensitivity or long-term irritation; in such cases, the medication should be discontinued, and in rare instances, ochronosis develops; the patient should discontinue Hydroquinone use and be referred to a clinician.
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Toxicity - No significant toxicity is reported with the topical use of the Hydroquinone cream. However, some studies reported malignancies in animals treated for extended oral doses.
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Hydroquinone in the Environment - Hydroquinone is a toxic chemical in both human and industrial activities. It increases the generation of reactive oxygen species and oxidative stress, increasing the potential for DNA damage. It is a crucial benzene metabolite that is hepatotoxic and carcinogenic. Studies show that Hydroquinone promotes tumor cell growth and suppresses the immune response. It is used in photography, dyes, paints, varnish oils, and motor fuels. Hydroquinone oxidized form is toxic and less degradable. It is highly toxic to aquatic organisms and rodents and causes leukemia, renal tubular cell tumor, and liver cancer. It also influences immune cell response and aggravates allergic reactions by increasing interleukin-4 production and immunoglobulin E levels.
Enhance Healthcare Outcomes:
The interdisciplinary healthcare team, including physicians, nurses, and pharmacists, plays a vital role in observing patients on Hydroquinone. To control the side effects, it is essential to monitor patients to ensure medication use as prescribed, but not for more than five to six months. Nursing staff plays a vital role in evaluating the patient and their compliance. It is necessary to follow the guidelines prescribed for the medicine application; frequency and adverse effects should be well explained to the patient. Patients are instructed to discontinue the medication if any irritation, hypersensitivity, or allergic reaction. Pharmacists need to review the use and adverse effects when dispensing the drug, check the need for refills, and inform the prescribing clinician in case of any concerns. The rare and harmful side effects of ochronosis should be explained to the patient using Hydroquinone, and they should be asked to discontinue the medicine immediately in case of side effects.
What Is the Efficacy of HQ?
Hydroquinone has to be prescribed at concentrations of two to five percent daily, with results seen after five to seven weeks. Treatment should be considered for at least three months and discontinued within one year. The efficacy of Hydroquinone's four percent cream was investigated in a comparative, placebo-controlled study of 48 patients with melasma. Patients were randomized to receive four percent or a placebo Hydroquinone cream twice daily and were instructed to use sunscreen daily for 12 weeks. Complete clearance of melasma was seen by 40% of the Hydroquinone group compared to ten percent of the placebo group. No severe side effects were reported, and the treatment was well tolerated.
Mechanisms to enhance the efficacy include the following.
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Triple combination creams (TCCs) containing Hydroquinone, corticosteroid, and retinoid allow greater doses of Hydroquinone and reduce irritation.
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Combining Hydroquinone 5 %, Tretinoin 0.1 %, and Dexamethasone 0.1 % for hyperpigmentation treatment was found to be more effective than the three treatments used as monotherapy.
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The retinoid helps prevent the oxidation of Hydroquinone, blends the melanin, thins the stratum corneum for better Hydroquinone penetration, and helps inhibit melanosome transfer. In addition, the steroid cream reduces irritation, which is seen if Hydroquinone concentrations of > 4 % are used.
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Hydroquinone 4 %, Tretinoin 0.05 %, and Fluocinolone acetonide 0.01 % were considered more efficacious and well-tolerated long-term.
Conclusion:
Hydroquinone is an efficacious treatment for multiple ranges of hyperpigmentation disorders and modifications of the original formula, which is still used with a relatively low AE profile. The fear of Hydroquinone after sporadic case reports can be prevented by careful supervision, limited treatment duration, and avoidance of compounding concomitant chemicals in other products. HQ is a practical, topical skin-lightening agent with a very safe profile. Careful explanations of the evidence should address the exaggerated fear of clients. EO is a rare occurrence that can be prevented by careful medical supervision, limiting the duration of exposure, and restriction surveillance in skin care to avoid adulteration with other offending substances.
