Adapalene is a Vitamin A derivative that is highly effective in reducing acne lesions. There is evidence to indicate that it also has potential in effacing wrinkles, lightening age spots and reducing actinic keratoses.


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments


Acne treatment


Better in treating non-inflammatory than inflammatory lesions. Useful as monotherapy, in combination therapy with antibiotics or as maintenance therapy.


Skin lightening


Lightened solar lentigines by decreasing epidermal melanin content.


Reduced actinic keratoses


Reduced the mean number of actinic keratoses after treatment lasting 9 months.


Rosacea treatment


Reduced the number of inflammatory lesions, but did not improve erythema or telangiectasia.


Wrinkle treatment


Lowered the number of wrinkles and improved the severity of forehead, periorbital and perioral wrinkles.


Increased skin hydration


Improved both transepidermal water loss and skin hydration.

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Table of contents:

1. Sources

Adapalene is a third-generation synthetic retinoid and a derivative of naphthoic acid.[1] It is not found naturally.

2. Bioavailability

Pharmacologically, adapalene behaves like tretinoin, but is chemically and photochemically stable.[2] Adapalene is also more lipophilic than tretinoin, which helps it to penetrate the skin.

Yet adapalene has very low percutaneous absorption once it has penetrated the stratum corneum -- one study demonstrated that only 0.01% of the applied dose penetrated through the skin.[3] Likewise, only trace amounts of adapalene have been found in the plasma of acne patients following chronic topical application.[4] This means that adapalene is entrapped in the epidermis, dermis and hair follicle, which is advantageous as it allows adapalene to exert maximal effect locally.[1]

Formulations of microparticles, microemulsions and soybean oil-cyclodextrin complexes have been developed to increase the therapeutic index of adapalene by enhancing its site-specific delivery to the pilosebaceous units, the target for topical acne delivery.[5][6][7][8]

Hair follicles are also attractive sites because they can act as long-term reservoirs for topically applied adapalene. Drugs in the hair follicles are depleted primarily through the slow process of sebum production and hair growth, in contrast to the stratum corneum, where they are continuously depleted due to desquamation.[6]

3. Effects on the skin

3.1 Acne vulgaris treatment

Numerous clinical trials have compared the efficacy of adapalene and tretinoin in treating acne vulgaris. A meta-analysis of five large studies with more than 900 patients over 12 weeks demonstrated that adapalene 0.1% gel is as effective as tretinoin 0.025% gel.[9] Adapalene also had a faster onset of action and considerably greater tolerability.[9] 2 other studies reached the same conclusion,[10][11] though a third was in favour of 0.1% adapalene, finding that it caused a greater decrease in total and non-inflammatory lesions than tretinoin.[12] It was later shown that adapalene is more effective on non-inflammatory rather than inflammatory lesions.[13] However, 0.1% tretinoin gel showed more rapid comedone reduction than 0.1% adapalene gel.[14]

Adapalene 0.1% gel is as efficacious as 0.05% isotretinoin gel and 0.1% tazarotene gel in the treatment of acne vulgaris,[15][16] but less effective than benzoyl peroxide 4% gel on both inflammatory and non-inflammatory lesions.[17]

Combination therapy with both adapalene and benzoyl peroxide is not superior to treatment with either adapalene or benzoyl peroxide alone.[13] On the other hand, the combination of 0.1% adapalene gel + doxycycline with or without benzoyl peroxide, was faster and more effective than doxycycline alone for severe acne.[18][19]

Adapalene is also useful in maintenance therapy following initial treatment with adapalene-doxycyline, adapalene-clindamycin or oral isotretinoin.[20][21][22]

Adapalene exerts its anti-acne effects through modulating cellular keratinization, the inflammatory process and microcomedo formation.[4][23]

An open-label study evaluating the effectiveness of adapalene 0.3% gel on photoaging discovered that 6 months of treatment resulted in significant improvements in the clinical grading of wrinkles, with a reduction in mean severity score of 40% in forehead wrinkles, 52% in periorbital wrinkles, and 29% in perioral wrinkles. The overall number of wrinkles was also significantly reduced. Melanin, the general skin tone, transepidermal water loss and skin hydration were also improved.[24]

Another study showed that solar lentigines were significantly lightened after just 1 month of twice-daily applications with 0.1% or 0.3% adapalene gel. After 9 months, 57% and 59% of the patients had lighter lesions in the adapalene 0.1% and 0.3% groups, respectively, in comparison with only 36% in the vehicle group.[25] Histological evaluations revealed a trend toward lower epidermal melanin after adapelene treatment, but the differences were not significant.[25]

3.3 Reduced actinic keratoses

Actinic keratoses are common epidermal lesions that have the potential to progress to invasive squamous cell carcinoma (SCC), with the highest incidence in the aged population.[26] They manifest as small erythematous scaly macules to pigmented rough patches to hyperkeratotic cutaneous horns in sun-exposed areas.[27]

Treatment with 0.1% or 0.3% adapalene gel for 9 months has been found to reduce the mean number of actinic keratoses.[25]

3.4 Rosacea treatment

Rosacea is a chronic inflammatory condition of the facial skin noted most commonly in northern Europeans. It manifests as erythema, papules, pustules, telangiectasias, and phymatous changes, with erythema intensifying during flares.[28]

One study comparing the efficacy of 0.1% adapalene gel with 0.75% metronidazole gel concluded that adapalene can be used as an alternative for topical treatment of papulopustular rosacea, as it is well-tolerated and significantly lowered the total number of inflammatory lesions. However, adapalene did not reduce erythema, unlike metranidazole.[29]

4. Side Effects

Adapalene has an excellent safety and tolerability profile. It has low irritation potential even when applied immediately to the skin after washing, in contrast to the delayed application recommended for other topical retinoids such as tretinoin and isotretinoin.[30]

Adverse events including erythema, dryness of the skin, itching and stinging may occur during the early treatment phase, but are usually mild or moderate in severity.[31] A year-long safety and efficacy study of 0.3% adapalene gel saw treatment-related, dermatologic adverse events experienced by 21% of subjects and dry skin, skin discomfort, and scaling reported by 10.5%, 8.3% and 3.3% of subjects, respectively.[32] Most of these side effects were mild or moderate, and the majority occurred in the first quarter of treatment.[32]

Adapalene is less irritating to the skin compared to tretinoin and isotretinoin,[9][14][15] but has comparable or better tolerability to tazarotene.[16] In fact, the irritancy potential for 0.1% adapalene cream and gel were significantly lower than that for tazarotene 0.1% cream, and not notably higher than that of the negative control.[33]

Unlike tretinoin, adapalene binds selectively to retinoic acid receptors β and γ, which translates to it causing less irritation of the skin.[34] It is also theorized that adapalene's lipophilicity leads to its dissolution in sebum after follicular penetration, thus preventing appreciable systemic exposure and toxicity.[35]

Scientific References

  1. Millikan LE. Adapalene: an update on newer comparative studies between the various retinoids. Int J Dermatol. (2000)
  2. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. (1993)
  3. Allec J, Chatelus A, Wagner N. Skin distribution and pharmaceutical aspects of adapalene gel. J Am Acad Dermatol. (1997)
  4. Irby CE, Yentzer BA, Feldman SR. A review of adapalene in the treatment of acne vulgaris. J Adolesc Health. (2008)
  5. Rolland A, et. al. Site-specific drug delivery to pilosebaceous structures using polymeric microspheres. Pharm Res. (1993)
  6. Bhatia G, Zhou Y, Banga AK. Adapalene microemulsion for transfollicular drug delivery. J Pharm Sci. (2013)
  7. Trichard L, et. al. Novel beads made of alpha-cyclodextrin and oil for topical delivery of a lipophilic drug. Pharm Res. (2008)
  8. Lauterbach A, Mueller-Goymann CC. Development, formulation, and characterization of an adapalene-loaded solid lipid microparticle dispersion for follicular penetration. Int J Pharm. (2014)
  9. Cunliffe WJ, et. al. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol. (1998)
  10. Grosshans E, et. al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. Br J Dermatol. (1998)
  11. Ellis CN, et. al. Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol. (1998)
  12. Cunliffe WJ, et. al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. J Am Acad Dermatol. (1997)
  13. Korkut C, Piskin S. Benzoyl peroxide, adapalene, and their combination in the treatment of acne vulgaris. J Dermatol. (2005)
  14. Nyirady J, et. al. A comparative trial of two retinoids commonly used in the treatment of acne vulgaris. J Dermatolog Treat. (2001)
  15. Ioannides D, Rigopoulos D, Katsambas A. Topical adapalene gel 0.1% vs. isotretinoin gel 0.05% in the treatment of acne vulgaris: a randomized open-label clinical trial. Br J Dermatol. (2002)
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  17. do Nascimento LV, et. al. Single-blind and comparative clinical study of the efficacy and safety of benzoyl peroxide 4% gel (BID) and adapalene 0.1% Gel (QD) in the treatment of acne vulgaris for 11 weeks. J Dermatolog Treat. (2003)
  18. Thiboutot DM, et. al. Combination therapy with adapalene gel 0.1% and doxycycline for severe acne vulgaris: a multicenter, investigator-blind, randomized, controlled study. Skinmed. (2005)
  19. Gold LS, et. al. Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis. (2010)
  20. Thiboutot DM, et. al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study. Arch Dermatol. (2006)
  21. Zhang JZ, et. al. A successful maintenance approach in inflammatory acne with adapalene gel 0.1% after an initial treatment in combination with clindamycin topical solution 1% or after monotherapy with clindamycin topical solution 1%. J Dermatolog Treat. (2004)
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  24. Herane MI, et. al. Clinical efficacy of adapalene (differin(®)) 0.3% gel in Chilean women with cutaneous photoaging. J Dermatolog Treat. (2012)
  25. Kang S, et. al. Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial. J Am Acad Dermatol. (2003)
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  27. Uhlenhake EE, et. al. Spreading pigmented actinic keratosis: a review. J Am Acad Dermatol. (2010)
  28. Two AM, Del Rosso JQ. Kallikrein 5-Mediated Inflammation in Rosacea: Clinically Relevant Correlations with Acute and Chronic Manifestations in Rosacea and How Individual Treatments May Provide Therapeutic Benefit. J Clin Aesthet Dermatol. (2014)
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