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Tretinoin

A Review of its Pharmacological Properties and Clinical Efficacy in the Topical Treatment of Photodamaged Skin

  • Drug Evaluation
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Abstract

Synopsis

Tretinoin (all-trans-retinoic acid) is a retinol (vitamin A) derivative which has been evaluated as a topical treatment for the symptoms of photodamaged skin. In several well-controlled clinical trials, the proportion of patients showing improvement was significantly higher with 0.01 or 0.05% tretinoin cream than with placebo for criteria such as global assessment, fine and coarse wrinkling, pigmentation and roughness. Improvements in the overall severity of photodamage were also significantly greater with tretinoin than with placebo. The extent of clinical improvement with tretinoin has generally been moderate, but cytological and histological studies have shown that extensive changes in the epidermis and dermis occur during treatment. However, the permanency and clinical significance of these changes has yet to be fully evaluated.

Topical tretinoin has also demonstrated potential for the treatment and eradication of premalignant skin growths such as actinic keratoses, and may be useful as combination therapy with fluorouracil in this indication.

Dermatitis (the retinoid skin reaction) is the most common adverse event experienced by patients receiving topical tretinoin; this condition may persist for up to 3 months, but is usually mild or moderate in nature.

Thus, topical tretinoin has been shown to be an effective form of treatment for the characteristic signs of photodamaged skin. Its ability to produce significant, albeit moderate, clinical improvements in symptoms such as fine wrinkling, roughness and pigmentation, together with its relatively mild or moderate adverse event profile, suggests that it is likely to be of considerable value in this indication. The treatment and eradication of potentially malignant growths such as actinic keratoses may also prove to be an important application for topical tretinoin.

Pharmacodynamic Properties

The effects of topical tretinoin on photodamaged skin have been described in numerous animal and human studies; they include thickening of the epidermis, compaction of the stratum corneum, increased collagen synthesis in the dermis, beneficial effects on melanocyte differentiation and distribution, promotion of epidermal hyperplasia and angiogenesis. Increases in epidermal thickening, a primary measure of the effects of tretinoin, ranged from 24 to 40% with 0.01 or 0.05% tretinoin, compared with 2 to 14% for placebo, in several well-controlled investigations involving patients with photodamaged skin. Most of the relevant pharmacodynamic data for tretinoin have been obtained during studies of 6 months’ duration or less. Preliminary evidence suggests that some effects are reduced after 12 months whereas others that are not evident at 6 months become apparent only with continued treatment; these findings and their clinical significance require clarification.

Data from several animal studies suggest that tretinoin may prevent the formation of skin tumours, although contradictory results suggesting enhancement of photocarcinogenesis have also been reported. The clinical significance of these results remains to be determined.

Pharmacokinetic Properties

Systemic tretinoin absorption from human skin after topical administration is low. Excretion of 3H-tretinoin in the urine and faeces accounted for 1.1 to 4.3% of a single topical dose given to healthy volunteers, and plasma concentrations were minimal compared with endogenous levels of tretinoin (8.5 to 34ng equivalents/L vs 1000 to 7000ng equivalents/L). In a separate study, tretinoin was not detected in plasma using a chromatographic/spectrometric assay (detection limit 2 μg/L) following single or multiple applications.3H-tretinoin was found in urine within 1 hour of topical application in healthy volunteers, with peak plasma levels recorded after 10 hours. Urinary excretion of tretinoin has been estimated to be between 0.1 and 5.9% of a single topical dose.

Clinical Efficacy

Several placebo-controlled clinical studies have demonstrated that topical tretinoin has significant efficacy in the treatment of photodamaged skin. Improvements in subjective global assessment scores were recorded in 49 to 100% of patients using once-daily 0.01% tretinoin, 68 to 100% of patients using 0.05% tretinoin and 0 to 44% of patients using placebo.

In 2 randomised, double-blind multicentre studies (n = 296 and 251), patient improvement rates for skin pigmentation, roughness and fine wrinkling were significantly better with 0.05% tretinoin than with placebo (total range 42 to 68% vs 22 to 47% and 59 to 86% vs 39 to 48%, respectively), as were reductions in the overall severity of photodamage (16.5 vs 6.9% and 27 vs 16.8%, respectively). Changes from baseline for several photodamage parameters were significantly greater with 0.05% tretinoin (11.9 to 37% reduction) than with placebo (3.2% increase to 20% reduction) in 251 patients with mild to moderate photodamage. Subjective improvements with tretinoin in these studies were supported by optical analysis of silicone impression skin replicas. Significant improvements in several periorbital and cheek parameters were noted with 0.01 and 0.05% tretinoin (≤20%) when compared with placebo (⪯5%).

Although topical tretinoin has been effective in the treatment or eradication of premalignant skin lesions (such as actinic keratoses, lentigines and dysplastic naevi), mainly in small numbers of patients, definitive efficacy data from well-controlled studies of large patient populations are lacking. Combination therapy with tretinoin and fluorouracil may be useful for the treatment of actinic keratoses.

Tolerability

Topical administration of tretinoin is frequently associated with a mild or moderate dermatitis-like condition which is characterised by dry, scaly, itchy skin and erythema (the retinoid skin reaction). These symptoms are generally transient, appearing from about a week to a few months after treatment initiation and lasting for up to 3 months, before declining despite continued application of the drug. The incidence of this condition in well-controlled clinical trials has ranged from 78 to 82% with 0.01% tretinoin and from 49 to 94% with 0.05% tretinoin. Additional effects experienced by patients receiving topical tretinoin include increased pinkness of the skin and inflammation of subclinical actinic keratoses.

Retinoids have been shown to be potent teratogens when given systemically but the potential for birth abnormalities after topical tretinoin use during pregnancy remains to be fully established. Although no increased incidence of birth defects has been reported during 2 decades of topical tretinoin use for acne, several reports of abnormalities have appeared more recently.

Dosage and Administration

Topical therapy with tretinoin is usually started with a cream formulation of between 0.025 and 0.1%, which is applied nightly to the face or forearm. Self-assessment of tolerance to tretinoin, and hence of the optimal administration regimen, is encouraged via patient monitoring of the irritation caused by the retinoid skin reaction. A slight peeling of the skin and erythema indicate an appropriate dose. The best clinical results are obtained when tretinoin is applied for several months or more. Topical tretinoin should not be used during pregnancy.

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Various sections of the manuscript reviewed by: J. Bhawan, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA; P. Buchan, CIRD Galderma, Sophia Antipolis, France; R. Caputo, Istituto di Scienze Dermatologiche, Universitá di Milano, Milan, Italy; J.M. Dayer, Division of Immunology & Allergy, Hôpital Cantonal Universitaire de Genéve, Geneva, Switzerland; S.H. Goh, International Skin Centre, Singapore; J.L.M. Hawk, St John’s Institute of Dermatology, St Thomas’ Hospital, London, England; A.M. Kligman, Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; G.L. Peck, Department of Dermatology, Washington Hospital Center, Washington, DC, USA; W.P. Raab, Allergy Clinic ‘City’, Vienna, Austria; H. Tagami, Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan.

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Noble, S., Wagstaff, A.J. Tretinoin. Drugs & Aging 6, 479–496 (1995). https://doi.org/10.2165/00002512-199506060-00008

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