Topical Retinoids in the Management of Photodamaged Skin: From Theory to Evidence-based Practical Approach

R. Darlenski; C. Surber; J.W. Fluhr

Disclosures

The British Journal of Dermatology. 2010;163(6):1157-1165. 

In This Article

Clinical Efficacy and Safety of Topical Retinoids in the Management of Skin Photodamage

Tretinoin

Of all the topical retinoids, tretinoin is the one that has been investigated most for clinical efficacy and safety. A number of reviews provide details of the study designs and endpoints, e.g. clincal signs of photodamage (fine and coarse wrinkles, mottled hyperpigmentation, sallowness), histolological features, and procollagen 1C synthesis (assessed immunohistochemically).[16,34,37–39] The pivotal studies of Kligman et al. [17–19] led to the implementation of vehicle-controlled and randomized studies. More than 20 randomized studies with tretinoin application in photodamaged skin have been published since 1986, either placebo-controlled or in reference therapy comparisons. In the following we address clinically relevant questions, such as

  1. duration of treatment,

  2. appropriate concentration, and

  3. adverse effects.

How Long should Tretinoin be Administered? Despite the beneficial effects of tretinoin on photodamaged skin, discontinuing treatment results in progression of the skin photodamage.[40] This raises the question of how long therapy should be continued. The clinical studies generally last between 1 month and 2 years, but mostly 6 months (12 studies). The long-term beneficial effects of tretinoin were first demonstrated at the clinical and histological level over a 22-month period.[41] Application of 0·05% tretinoin cream, once daily for 24 months, resulted in an improvement of photodamage which continued until the end of the study.[42] No histological signs of cellular atypia were noted during the study. In addition, application of 0·05% tretinoin cream three times per week sustained the improvement achieved in the initial treatment phase.[43,44] In summary, initial treatment with tretinoin should be followed by a long-term maintenance phase of retinoid application, maybe at a lower concentration and/or with less frequent applications. Nonetheless, further placebo-controlled, double-blind studies are needed to prove the validity of this therapy schedule.

What is the Optimal Tretinoin Concentration? A dose-dependent therapeutic effect of tretinoin has been demonstrated.[43,44] Other authors could not establish a difference in the clinical or histological appearance after the application of different tretinoin concentrations (48 weeks, 0·025% vs. 0·1% tretinoin cream),[45] even though the higher concentration caused more pronounced irritation. Thus the hypothesis that the retinoid action in photodamaged skin is due to induced irritation has to be revised.

High-strength tretinoin (0·25%) was used for rapid 'retinization' of photoaged skin.[46] Interestingly, the adverse effect diminished and the formulation was better tolerated and more effective over time. Using lower dose tretinoin creams (0·01% vs. 0·05%) in the 6-month extension phase after the initial 6 months of once daily treatment (with the same dose regimen) resulted in greater improvement.[47] However, subjects using the 0·01% formulation did not reach the level of response seen with the higher concentration.

The concentration of tretinoin most frequently used in clinical studies was 0·05%. However, two multicentre, randomized, double-blind, vehicle-controlled clinical studies lasting 24 months showed that 0·02% tretinoin cream was effective and well tolerated.[48] Use of tretinoin in concentrations of 0·01% and lower is questionable as no difference was demonstrated between subjects treated with 0·01%, 0·001% and vehicle.[43] Overall, 0·025% may be considered therapeutically effective with a reasonable safety profile.

Adverse Effects of Tretinoin Treatment – how Can they be Diminished? Adverse events of retinoid therapy include systemic and local effects.

Systemic adverse events: Since its introduction as a topical drug, no systemic adverse effects have been reported for topical tretinoin application (reviewed in reference[16]). Topical tretinoin (either single-dose or long-term treatment) did not affect the endogenous levels of tretinoin or its metabolites.[49] The results were attributed to the insignificant systemic absorption of approximately 2% of the applied dose. The experimental data were supported by an epidemiological study on fetal malformation and topical tretinoin use in the first trimester of pregnancy.[50] The prevalence of anomalies among babies of exposed women was 1·9% compared with 2·6% among babies of nonexposed women. In addition, no correlation between holoprosencephaly and topical retinoid use during pregnancy was revealed retrospectively.[51] Nevertheless, pregnant women are generally advised to cease tretinoin treatment during pregnancy, and to avoid pregnancy during tretinoin treatment.

Local adverse effects of tretinoin treatment include the 'retinoid reaction', also known as 'retinoid dermatitis', as well as exaggerated photosensitivity at the beginning of the treatment. Results from four prospective, randomized, controlled trials in healthy volunteers showed that tretinoin is neither phototoxic nor photoallergenic.[52] Several strategies to diminish and/or prevent the adverse effects of tretinoin application have been suggested and can be summarized as follows:

Dosing related

  • Once daily application, in the evening

  • Less frequent application if moderate to severe irritation occurs, i.e. alternate days or three times a week

  • Possible concomitant application of 3% indomethacin and/or 1% hydrocortisone to relieve the irritant reaction[53]

Patient related

  • Discovering the patient's expectations of therapy

  • Explaining and discussing the expected outcomes, course and duration of treatment

  • Discussing the adverse effects, such as the 'retinoid reaction', before starting treatment.

Accompanying measures

  • Appropriate dermal moisturization, at least 30 min after the retinoid application

  • Application of sunscreens during daytime

In addition to the practical considerations, novel topical delivery systems such as liposomes, controlled-delivery systems, and nanoparticles have been developed with the aim of diminishing the adverse effects of treatments.[54,55] Furthermore, several natural compounds, such as gingko extracts, cola extract, and beta-sitosterol, might have some potential to antagonize the irritative effect of retinoids.[56]

A recent study in 1131 veterans disclosed an association of topical tretinoin therapy with all-cause mortality.[57] A former study propounded that topical tretinoin use can be associated with pulmonary disease-related death.[58] No specific cause of death could be outlined against all the causes of death in the veterans study.[57] Additionally, tretinoin use and smoking taken together had no statistical interaction on the increased mortality. The lack of dose–response association (number of tubes of cream used) together with the data on the minimal systemic tretinoin absorption challenged the causal relationship between topical tretinoin use and death. Nevertheless these reports will make it unavoidable for the pharmaceutical industry to exclude the potential adverse effects of generic or innovator retinoid products in this indication.

Isotretinoin

After the first report on clinical improvement of photoaged skin with isotretinoin,[59] two vehicle-controlled studies revealed the beneficial effects of topical isotretinoin.[60,61] In both studies, after the initial application of a 0·05% formulation, the concentration of isotretinoin was increased to 0·1% in the second part of the study.[60,61] Despite the higher strength, the formulation was well tolerated and did not cause significant irritation. Treatment response in photodamaged skin increased throughout the 36-week treatment with 0·1% isotretinoin cream (multicentre, randomized, vehicle-controlled trial).[62] Furthermore, the combination of isotretinoin 0·5% with a sunscreen improved photodamaged skin, as shown by profilometry, and was well tolerated by the subjects (n = 346).[63]

Tazarotene

Tazarotene 0·1% gel was effective in reducing skin roughness and fine wrinkling, improved skin hydration, and corrected epidermal atrophy and keratinocyte atypia.[64] Later, further histological effects of tazarotene, such as an increase in epidermal thickness, and compaction of the stratum corneum were documented.[65] The efficacy of different concentrations of tazarotene was studied and compared with 0·05% tretinoin.[66,67] A more rapid response to tazarotene was noted (weeks 12 and 20).[66] However, at the end of the treatment period there was no difference in overall improvement between tretinoin and tazarotene. The local adverse reactions were generally graded as mild or moderate, with a concentration-dependent increase.[66,67] A 24-week multicentre, double-blind, vehicle-controlled study followed by a 28-week open-label extension demonstrated the long-term benefits of tazarotene 0·1% cream.[68,69] Clinical improvement continued with tazarotene treatment and had not reached a plateau by week 52. In addition, there was no systemic accumulation of the drug and the plasma level of tazarotenic acid was below that of endogenous retinoids.[68] The multifactorial effects of tazarotene were confirmed recently.[70] The authors concluded that the application of tazarotene 0·1% cream once daily is effective in ameliorating signs of photodamage.

Retinol and its Derivatives

Topical retinol (vitamin A) showed beneficial effects in influencing the pathogenesis of cutaneous photodamage, e.g. inducing epidermal thickening, reducing MMP expression and increasing collagen synthesis, although it was 20-fold less potent than RA.[13,33] On the other hand, retinol is less irritant than its natural metabolite RA.[71] However, retinol is very unstable and degrades easily into inactive metabolites.

Retinol derivatives such as retinyl propionate and the N-formyl aspartame derivative have been proposed as anti-photoageing agents, as they are more stable and have shown some beneficial effects in experimental studies.[72,73] However, data from clinical controlled studies with retinol derivatives are either sparse or nonexistent.

Retinaldehyde, a naturally occurring precursor of RA and retinol metabolite, has biological activity and good tolerability in the treatment of skin photodamage.[74] Topical 0·05% retinaldehyde is effective in improving signs of photodamage, as demonstrated by ultrasound and rheological techniques in a prospective, vehicle-controlled study.[75] Optical profilometry showed that retinaldehyde as well as RA (both 0·05% creams) induced significant reduction of wrinkles and roughness in photoaged skin.[76] Retinaldehyde was better tolerated than its metabolite, RA.

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