40 Years of Topical Tretinoin Use in Review

June 2013 | Volume 12 | Issue 6 | Original Article | 638 | Copyright © June 2013

Hilary E. Baldwin MD,a Marge Nighland BS,b Clare Kendall MA,c David A. Mays PharmD MBA,c Rachel Grossman MD,b,c and Joan Newburger PhDc

aSUNY Downstate Medical Center, Brooklyn, NY bValeant Dermatology, a subsidiary of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ cJohnson & Johnson Consumer & Personal Products Worldwide, Skillman, NJ

reduce pigmentation through increasing keratinocyte turnover and diminishing tyrosinase activity.17 Tretinoin reverses thickening of stratum corneum and abnormal desquamation of keratinocytes.18,19 Induction of RARβ expression has also been shown to suppress carcinogenesis in a number of squamous cell tumors, including cancers of the lung, esophagus, and breast.20-25

The Treatment of Acne Vulgaris

Decades of research have established topical tretinoin as a first-line treatment for AV.26 Its mechanisms of action for the treatment of acne may be mediated by its effects on reducing horny-cell adhesion, increasing epidermal-cell turnover, and increasing mitotic activity, thereby reducing comedone formation.14,27-29 The use of topical tretinoin has been shown to reduce total acne lesion counts26,30 and may also reduce acne-related inflammation.10,31,32 In addition, topical tretinoin is recommended as maintenance therapy for acne, particularly because it reduces comedone formation without inducing bacterial resistance.29,33,34

Acne Vulgaris Clinical Studies

The following is a brief summary of key representative trials of tretinoin formulations in patients with AV.
The efficacy and safety of tretinoin gel 0.05% for adults with mild to moderate acne was studied in 2 12-week, prospective, multicenter, randomized, vehicle-controlled studies of patients aged 10 years or older with mild to moderate acne; those who applied topical tretinoin once daily showed significant improvement by week 12 in global acne severity and mean percent reductions in total lesions compared with those using vehicle (43% vs 22% and 35% vs 19%, respectively).35,36 The most common adverse events ([AEs]; incidence ≥5%) observed were dry skin, peeling/scaling/flaking skin, burning sensation in the skin, and erythema.35,36 A tretinoin microsphere gel (TMG) 0.04% and 0.1% formulation, developed to reduce the irritation potential associated with the use of topical tretinoin, was effective at reducing acne lesions over 12 weeks (some added benefit for tretinoin 0.1% vs 0.04% was observed at week 2) and was associated with only mild cutaneous irritation in most patients.37 Tretinoin microsphere gel 0.04% applied nightly was also shown in 3 randomized, double-blind, vehicle-controlled studies to be well tolerated and more effective than vehicle over 12 weeks in treating adolescents and adults (aged 11-49 years) with mild to moderate facial acne.38
Currently, topical tretinoin is often used in combination with other therapies for acne management, in particular with clindamycin and benzoyl peroxide (BP).32,39,40 Numerous studies of tretinoin in combination with clindamycin have been conducted. For example, in one 12-week, multicenter, randomized, blinded study of 1,649 subjects aged 12 years or older, the combination of clindamycin phosphate 1.2% and tretinoin gel 0.025% was compared with each component separately, as well as with vehicle alone. Mean total lesion-count reduction for the combination treatment, clindamycin alone, tretinoin alone, and vehicle was 55%, 49%, 51%, and 39%, respectively.41 Combined, local AEs for subjects receiving tretinoin/clindamycin gel in this and 2 other studies of the same formulation included dryness, irritation, exfoliation, erythema, pruritus, dermatitis, and sunburn.28,41,42
Other research has shown that combination regimens of a TMG pump (0.04%) and BP (5% wash)43 or fixed combinations of tretinoin gel (0.025% to 0.04%), clindamycin (1% to 1.2%), and BP (5% wash) are efficacious and tolerable for treating moderate to severe AV.39 New regimens and formulations of topical tretinoin have been developed because it was found that BP has the potential to degrade tretinoin and that tretinoin is unstable in visible and UV light.43 The TMG formulation has been shown to be significantly more photostable, both alone and in combination with BP and erythromycin, compared with a nonmicrosphere formulation.44-46

The Treatment of Photodamage and Melasma

As noted above, Kligman and colleagues47 studied topical tretinoin for the treatment of photodamage. In this study, topical tretinoin 0.05% treatment for 3 to 12 months was shown to partially reverse both clinical and histological signs of photodamage. Among patients treated with tretinoin, histology demonstrated replacement of atrophic epidermis via hyperplasia; elimination of dysplasia, atypia, and actinic keratoses; dispersion of melanin granules; collagen formation; angiogenesis; and exfoliation of retained horn in the follicles.47
Other double-blind, controlled, and open-label studies in the United States and Europe have confirmed these findings in photodamaged skin. Both shorter-term (1-4 months) and longer-term (6-54 months) trials showed improvement in clinical signs of photodamage with topical tretinoin, including fine and coarse wrinkling, hyperpigmentation, roughness, and overall severity of photodamage.48-50 Application with tretinoin prior to UVB irradiation inhibited the induction of skin metalloproteinases (including collagenase, 92-kd gelatinase, and stromelysin-1), which are induced by UV radiation and degrade skin collagen, thereby contributing to photodamage.12
Topical tretinoin (0.05% to 0.1%) has been shown to reduce hyperpigmentation associated with UV exposure, both alone and in combination with hydroquinone, intense pulsed light, or glycolic peels, as well as in triple-therapeutic combinations (tretinoin plus hydroquinone and triamcinolone acetonide) for hyperpigmentation conditions such as melasma.14,51,52 Topical tretinoin is currently indicated as a part of combination therapy (with fluocinolone acetonide and hydroquinone) for treatment of melasma.14,52,53 The mechanism of action for clinical improvement in melasma has been suggested to be inhibition of tyrosinase, and it also has been shown, when used in combination, to facilitate epidermal penetration of hydroquinone.14,17,51,53