40 Years of Topical Tretinoin Use in Review

Recently, findings have provided further evidence that topical tretinoin may both reverse photodamage and play a role in chemoprevention: 2 case reports using low-concentration tretinoin gel (0.05%) over 4 weeks showed both a reversal of photodamage and chemopreventive benefits.⁵⁴

Historically, use of topical tretinoin has been limited in some patients due to associated AEs, including skin-irritation (dryness, tightness, and erythema) and possible heightened sunburn potential; however, the variations seen in these AEs may be based on formulation, as well as frequency and mode of application.^29,55,56 Cutaneous irritation can be mitigated by inhibiting retinoid penetration into the deep epidermis and dermis, as with slow-release tretinoin formulations (ie, TMG).⁴⁴

One study showed an increased risk for lung cancer associated with topical tretinoin use.⁵⁷ In the Veteran’s Affairs Topical Tretinoin Chemoprevention Trial, topical tretinoin was associated with an increased risk of all-cause mortality. However, post hoc analyses showed that there were other important predictors of death, including smoking, age, and comorbidities,58 and a recent review found no other evidence of noncutaneous AEs associated with topical tretinoin.⁵⁹

Due to the similarity of tretinoin to isotretinoin, a known human teratogen, there has been concern that the use of topical tretinoin during pregnancy may cause developmental malformations in the fetus. At least 4 case reports have been published linking congenital abnormalities with maternal use of topical tretinoin.^60-64 However, a retrospective study of 215 pregnant women exposed to topical tretinoin showed no increased incidence of retinoid embryopathy compared with 430 age-matched controls.⁶⁵ Furthermore, 2 prospective studies in 200 women who reported exposure to topical tretinoin during the first trimester of their pregnancies found that this exposure was not associated with increased risk for congenital malformations or retinoid embryopathy.^66,67 Despite the fact that the evidence is inconclusive, women are generally advised to avoid exposure to topical tretinoin during pregnancy.^66,67 Additionally, there is remarkably little percutaneous absorption of topical tretinoin (<2%) after single and repeated application (28 days and >1 year) of topical tretinoin (0.05% tretinoin emollient cream and 0.1% tretinoin gel) and its metabolites (13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid).^68,69

As noted, topical tretinoin has been studied in many other conditions outside of its approved use in acne and photodamaged skin.

To identify reports of tretinoin use outside of acne and photodamage, an electronic search was conducted in MEDLINE (via PubMed) for all studies, including case reports. Search criteria were: 1. “Tretinoin” [MeSH] AND “Administration, Topical” [MeSH] and NOT “Acne” and NOT “Photodamage”; 2. “All-trans retinoic acid” and “Administration, Topical” [MeSH] and NOT “Acne” and NOT “Photodamage.” References and review articles were reviewed manually to identify other relevant studies. Following are highlights of the search results. Results are included below and in the Table.

Topical tretinoin cream may be effective in reducing actinic keratosis (compared with baseline), both alone and as an adjunct to 5-fluorouracil, possibly due to its ability to suppress epidermal proliferation and normalize differentiation (although data are based on a limited number of patients). ^70-78 Topical tretinoin may also have a chemopreventive role in patients at high risk of developing keratinocyte carcinomas.⁷⁸

Research outcomes demonstrate the potential for topical tretinoin to be used to reverse and reduce dysplastic nevi.^79-84 Topical tretinoin has been shown to eliminate dysplastic nevi or revert them to a benign state.^81-83 Tretinoin may induce apoptosis in melanoma cells by targeting mitochondrial dysfunction.⁸⁵

Blinded, placebo-controlled, open-label prospective studies and case studies have demonstrated histological and clinical improvements in striae distensae with topical tretinoin, although findings are equivocal.^86-91 Collagenesis and increased epidermal proliferation induced by tretinoin may be associated with improvements in scarring and keloids.^19,86,89

Prospective observational findings indicate that tretinoin delivered via collagen sponge and cervical cap may have the potential to treat moderate to severe cervical dysplasia (CIN II/III).^92-97 However, one 12-week, placebo-controlled clinical trial failed to show a difference between patients with cervical dysplasia treated with topical tretinoin and those treated with placebo.⁹² Chemopreventive effects of tretinoin might be attributed to the effect of tretinoin on cell proliferation, differentiation, and cell death.⁹²

A randomized study suggested potential for tretinoin therapy to improve foot ulcers in patients with diabetes.⁹⁸ Pretreatment with tretinoin cream was shown to reduce healing time in 2 studies (ie, healing following electroepilation and after a chemical peel).^99,100 Histological analyses also demonstrated significant healing of wounded skin with topical tretinoin treatment.^101,102 The beneficial effect in wound healing may be associated with the ability of topical tretinoin to enhance collagen production, stimulate fibroblasts, and increase angiogenesis.^99,103