Tretinoin

What tretinoin is

Tretinoin (all-trans retinoic acid) is a retinoid, that is, a derivative of vitamin A, for use on the skin. In Germany it is prescription-only and approved, for example, as a 0.05 % cream for acne vulgaris; according to the summary of product characteristics, it is applied thinly once or twice daily. In Germany it is not approved for skin aging.

In the US, a 0.02 % cream is explicitly approved as an adjunct for fine facial wrinkles, embedded in skin care and consistent sun protection. What is rated is the state of knowledge: for acne and photoaging there are randomized trials, tissue samples and decades of use.

How it works

Tretinoin binds to retinoic acid receptors in the cell nucleus and thereby changes which genes are read in skin cells. In acne, it targets the disturbed keratinization in the hair follicle.

In sun-damaged skin, tissue samples under tretinoin showed a thicker epidermis, a more compact horny layer and less melanin. In a two-year study, a marker of new collagen formation rose in the dermis without any increase in abnormal cell changes. The chain of action is therefore well described in humans.

What the studies show

Weiss 1988: the first blinded study

Weiss 1988 (JAMA) treated one forearm with tretinoin and the other with cream without active ingredient for 16 weeks; on the face, half received tretinoin and the other half the comparison cream. All 30 participants who completed the study showed improvement on the treated forearm, not on the comparison arm. On the face, the skin improved in 14 of 15 under tretinoin and in none under the comparison cream. The side effect was skin irritation.

Olsen 1992: three concentrations

Olsen 1992 (J Am Acad Dermatol) compared three tretinoin concentrations with cream without active ingredient over 24 weeks in 296 participants with sun-damaged facial skin. Under 0.05 %, the skin improved in 68 %, under the comparison cream in 43 %; a good or very good result was seen in 26 % versus 11 %. The two lower concentrations did not differ significantly from the comparison cream. Redness, peeling and burning were mostly mild to moderate.

Kang 2005: two years

Kang 2005 (Am J Clin Dermatol) treated 204 participants with moderate to severe photoaging for up to two years with 0.05 % cream or placebo. Fine and coarser wrinkles, pigment spots, age spots and sallow skin improved more than under placebo (p < 0.05). Tissue samples showed no increase in abnormal skin or pigment cells; a marker of new collagen formation rose after twelve months (p = 0.0074).

Huang 2023: acne treatments compared

Huang 2023 (Ann Fam Med) analyzed 221 randomized trials with 65,601 participants on acne treatment. The most effective were isotretinoin tablets, followed by triple combinations of a topical retinoid, benzoyl peroxide and an antibiotic. As single agents, topical retinoids worked about as well as antibiotics on inflammatory lesions.

Where the data stop

• How large the effect is. Even under cream without active ingredient, the skin improved in 43 % of participants. The US prescribing information states that many in the comparison group achieved the desired improvement in fine wrinkles with skin care and sun protection alone.
• Deep wrinkles and rejuvenation. For the 0.02 % cream approved in the US, no effect on deep wrinkles, sagging, age spots or pigment spots has been shown. According to the approval, it does not eliminate wrinkles, does not repair sun damage and does not reverse skin aging.
• Duration. In the US approval, daily use for more than 52 weeks is considered insufficiently studied. One placebo-controlled study ran for two years.
• UV and skin cancer. In mouse experiments, tretinoin may have enhanced the tumor-inducing effect of UV radiation; this has not been studied in humans. People with a history of skin cancer were excluded from the US approval studies.

Status, approval and legal

Tretinoin is prescription-only in Germany (Medicines Prescription Ordinance). It is approved as a cream for acne vulgaris, for example at 0.05 %. There is no approval in Germany for skin aging; use for that purpose is an off-label use and belongs in the hands of a physician.

In the US, tretinoin cream 0.02 % is approved as an adjunct for softening fine facial wrinkles, under medical supervision and together with sun protection.

A European review of retinoids determined in 2018 that topical retinoids, too, must not be used in pregnancy or by women planning a pregnancy. Absorption through the skin is considered low; the rule is a precautionary measure. Warnings about psychiatric side effects apply only to oral retinoids.

Safety

Common are redness, peeling, burning, stinging, dryness and itching, especially at the start; according to the summary of product characteristics, they usually decrease over time. At the start, acne may temporarily worsen. The skin becomes more sensitive to light, which is why the summary of product characteristics advises avoiding sun and tanning beds and protecting treated skin.

Tretinoin is contraindicated in pregnancy and when planning a pregnancy; if a pregnancy occurs during use, treatment must be stopped. During breastfeeding it must not be applied to the breast area.

The safety value of 8 in the BK-Score rates the data, not the danger.

Sources

• Weiss JS et al., JAMA 1988 – tretinoin improves photoaged skin, double-blind study
• Olsen EA et al., J Am Acad Dermatol 1992 – tretinoin cream in three concentrations versus vehicle, 296 participants, 24 weeks
• Kang S et al., Am J Clin Dermatol 2005 – tretinoin 0.05 % versus placebo over two years, 204 participants
• Huang CY et al., Ann Fam Med 2023 – network meta-analysis of 221 randomized trials on acne treatment
• Summary of product characteristics Cordes VAS 0.5 mg/g cream (tretinoin, as of July 2024)
• US prescribing information Renova (tretinoin cream 0.02 %), DailyMed
• EMA, review of retinoid-containing medicines 2018 – pregnancy prevention and topical retinoids
• German Medicines Prescription Ordinance (AMVV), Annex 1 – tretinoin