Skincare Ingredients: Tretinoin, Adapalene, and Tazarotene – part one

Note: This post is meant to discuss topical retinoids as ingredients.  I will be writing an additional post on how to best use Differin .1% (OTC) at a later date, as I am two weeks deep into using it now. In addition, this post only covers the effects of topical retinoids in acne. Please stay tuned for more posts about retinoids and wrinkles and scarring!

Topical retinoids are one of the most common treatments for acne – both during treatment and for maintenance, after the acne is considered to be resolved. During treatment, they are most often prescribed in combination with other products, such as benzoyl peroxide (BPO), where they show the most efficacy.

While the pathogenesis of acne is constantly evolving, it is widely accepted that the key factors that play a role in the development of acne are follicular hyperkeratinization, microbial colonization with p. acnes, sebum production, and inflammation. Additional factors have been suggested by the American Academy of Dermatology (AAD), such as “neuroendocrine regulatory mechanisms, diet, and genetic and nongenetic factors all may contribute to the multifactorial process of acne pathogenesis.” To understand how retinoids can improve acne, you need to first understand some of the mechanisms of acne, particularly follicular hyperkeratinization.

According to William J Cunliffe (Acne: Diagnosis and Management, 2001):

Acne lesions do not usually occur in a follicle bearing a terminal hair [hairs found on the scalp, for example]. The hair acts as a wick allowing sebum to drain from the pilosebaceous canal. In contrast, in the pilosebaceous follicles the hairs are small and vallus in nature and often do not reach the surface. They are ineffective wicks and do not therefore prevent the retention of follicular contents. Histological examination of the pilosebaceous canal reveals that much of the duct comprises an epidermis-like structure undergoing cornification [the final stage of keratinization for the skin cells], the cornified material occupying the more central part of the canal. … The horny cell layers [the stratum corneum is frequently referred to as the horny layer] … soon desquamate [shed] into the central part of the canal to form a heterogeneous [diverse] mass together with sebum and bacteria. … Thus the horny cells distend the pilosebaceous canal, first producing a microcomedone and then a clinical lesion. It is not known why some lesions remain closed comedones (whiteheads) and why other lesions progress to open comedones (blackheads). As the comedones enlarge, the sebaceous gland may atrophy but sebum continues to be produced until the glands are totally replaced. 

In short, the hair of the face is too short and too fine to drain sebum (oil) effectively, which allows the follicles to retain its contents, including skin cells that line the hair follicle that would otherwise be shed normally. This forms a clumpy mass of sebum, bacteria, and shed skin cells, which turns into a microcomedone and from there, a closed or open comedone. Why this occurs is not very well understood, but it is thought to be due to hormones, abnormal lipid compositions, or microbial factors.

In addition to this, it has been found that the follicular cells in patients with acne is more irregular. This favors retention of shed cells. As the lesions mature into a microcomedone, the walls of the follicle become patchy and thin.

acne_histology

However, this has become the basis for retinoid usage, and has placed retinoids at the core of topical therapy for acne due to their comedolytic behavior, which allows them to resolve the precursor to lesions (microcomedones), as well as their mild anti-inflammatory properties.


An Introduction to Retinoids

Retinoids have been used since the 1960s, when they were discovered to have tremendous effects on disorders of keratinization. They work by binding to specific receptors on the cells, and each retinoid binds to a different set of retinoic acid receptors. In tretinoin, they bind to alpha, beta, and gamma receptors, while tazarotene and adapalene selectively bind to beta and gamma receptors. This is what makes each retinoid’s activity on the skin (as well as tolerability) a bit different.

Again, to quote William J Cunliffe:

The activation and inhibition of certain steps of gene transcription results in changes of different pathways. These pathways include proliferation, differentiation, inflammation, and sebum production. … Some retinoids such as tretinoin increases the mitotic activity of the ductal keratinocytes …

In short, these ingredients are cell-communicators that can result in changes to the skin, such as increased cell turnover, reduced sebum production, and more normalized cell shapes.

All retinoids are vitamin A derivatives. There are three major types of topical retinoids available today, which include:

  • Tretinoin (Brand name Retin-A)
    • The first topical retinoid and the gold standard.
    • Available in gels or creams, and is now in less irritating microsphere formulations such as Retin-A Micro.
    • Available in gel and cream .025% and .1% strengths
    • Also available in combinations with topical clindamycin (.025% tretinoin/1.2% clindamycin phosphate)
  • Adapalene (Brand name Differin)
    • One of the best studied retinoids for combination treatments with BPO. Much better tolerated than tretinoin in most cases.
    • Available in .1% gel over-the-counter in the US
    • Available in .1% or .3% creams and .1% lotion
    • Available as combination a with BPO (Epiduo, .1% adapalene, 2.5% BPO)
  • Tazarotene (Brand name Tazorac)
    • Potentially more efficacious than tretinoin at treating papules and open comedones.
    • Stronger than adapalene (Differin)
    • Can be used to treat psoriasis
    • Available in gels, creams, or foams in .05% and .1% strengths

They all carry many of the same side effects of peeling, dryness, erythema (redness), and irritation, and the higher the concentration of the retinoid, the higher the risks of side effects become. In 2016 Guidelines for the Management of Acne, the AAD also notes about combinations with BPO:

Some formulations of tretinoin (primarily generic products) are not photostable and should be applied in the evening. Tretinoin also may be oxidized and inactivated by the coadministration of BP. It is recommended that the 2 agents be applied at different times. Tretinoin microsphere formulation, adapalene, and tazarotene do not have similar restrictions.

Topical retinoids have also been associated with photosensitivity and all people who are using them should use at least SPF 30-50 every day to avoid burns and sun damage, which reverse many of the benefits of retinoids. You should also avoid the eye area, including lids and beneath the eye, as well as the lips and the areas next to the nasal passages. Dr Dray recommends using Vaseline on these areas and calls it “greasing the orifices,” which I quite like.

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A Note About Antibiotics and Topical Antibiotic Usage

Since many of the retinoid studies I am about to discuss are those which have been conducted in combination therapies (over 16,000 studies have been published around combination therapies), I think it is both unavoidable to discuss antibiotic resistance and its effects on how doctors are now prescribing topical acne treatments.

As you probably already know, antibiotic resistance is a growing public health concern in virtually all parts of the world. While antibiotics have been considered a fantastic treatment for acne for a long time, primarily due to their anti-inflammatory effects, nonantibiotic agents, particularly BPO, has been advised for combination treatments due to the highly effective nature of BPO to kill p. acnes without creating bacterial resistance.

Antibiotic resistance can change the outcomes of acne treatments, and in a 1998 review, there was a “clear association between poor therapeutic response and antibiotic-resistance propionibacteria [p. acnes].” (Source) The Global Alliance to Improve Outcomes in Acne (which I will be abbreviating to GAIOA from now on) also notes that resident flora has a “memory” “and retains resistance variants long after antibiotic therapy is discontinued.” Worse, this can lead to other complications down the line:

Patients with acne are often treated with multiple antibiotics and their flora is exposed to a significant selective pressure for resistance development. Margolis et al found that patients with acne treated with antibiotics had 2.15 times greater risk of developing an upper respiratory tract infection compared with patients with acne who were not treated with antibiotics. In addition, there have been an increasing number of reports of infections caused by P. acnes, including arthritis, endocarditis, endophthalmitis, and adenitis. … several researched have termed P. acnes infections ‘an emerging clinical entitity’ and ‘an underestimated pathogen.’ 

To put this into perspective, one 12-week study involving 208 patients with acne treated with topical erythromycin showed erythromycin-resistant staph on the face increase from 87% to 98% while the density of the organism increased significantly.

Because of this, it is suggested that most clinicians only prescribe short-round antibiotic usage – 3 to 4 months – and only if absolutely necessary. For the patients who do require antibiotics, especially longer term antibiotic usage, it is very important that your doctor monitor your progress in order to prevent resistances.


Evidence for Combination Therapies

Combination therapies involving retinoids plus an antimicrobial agent have been used since the 1970s, with many early studies showing that retinoids, when used in addition to antimicrobials such as topical BPO, were much more effective than those who were using the antimicrobials alone. While early studies were mostly conducted with topical tretinoin plus oral tetracycline, 67% of patients vs 48% of those treated with tretinoin alone and 41% of those treated with tetracycline alone had “good to excellent” outcomes.

Combination therapies are most broadly recommended for people with mild to moderate acne, as per the AAD:

1-s2.0-S0190962215026146-gr1_lrg

Most modern combination treatments combine clindamycin and BPO along with a topical retinoid. This combination not only increases the likelihood of a positive outcome, but also decreases the development of resistant strains of bacteria due to topical antibiotics.


Treatment with Combination Therapies

For all of the following therapies, I have included the prescribing information as provided by the American Academy of Dermatology (2016). You should always follow your doctor’s instructions, but I also know some of you may be acquiring these prescription drugs without a doctor for any number of factors, and I feel like you have a right to this information. Please use it responsibly.

Adapalene (Differin and Epiduo)

In 2007, a study of Epiduo (0.1% adapalene and 2.5% BPO) was conducted. According to the GAIOA, “It is thought that adapalene and BPO have synergistic actions, because BPO is the most potent bactericidal agent against p. acnes and adapalene, like other retinoids, is comedolytic and anticomedogenic.” A double-blind study of adapalene/BPO in 517 patients with moderate to moderately severe acne also showed significantly lower lesion counts than patients treated with the vehicle alone (the formula the drug is carried in) or placebo.

The once-daily fixed-dose combination formulation of adapalene/BPO has also been evaluated during 12 months in 452 patients with acne. The fixed-dose combination had good safety with only mild to moderate adverse events that typically occurred in the first 1 to 2 months after initiation of therapy and resolved spontaneously. 

The regimen of adapalene plus BPO and clindamycin products has also been studied, with reduction of lesions apparent as early as week two.

adapaleneadapalene_bpo

Tazarotene (Tazorac)

While Tazorac (or “Taz”) has not been formulated in a combination product like Adapalene (Epiduo), it has been studied in combination with BPO and 3.0% erythromycin/5% BPO. In a study of 440, investigator-masked, randomized, parallel group study, tazarotene plus erythromycin/BPO was “significantly more effective” than other regimens including tazarotene, such as tazarotene and clindamycin.

taz

Tretinoin (Retin-A, Retin-A Micro, Veltin, Ziana)

Tretinoin is one of the most widely studied of the retinoids, and has significant evidence to back it up in use with combination studies.

Bowman reported the results of a controlled trial comparing three treatments: (1) clindamycin/BPO gel; (2) clindamycin/BPO gel plus tretinoin 0.025% gel; and (3) clindamycin/BPO gel plus tretinoin gel 0.025% plus clindamycin. In this study, the triple combination was most effective in reducing inflammatory lesions (69%) followed by clindamycin/BPO (66%), then tretinoin plus clindamycin (52%); non-inflammatory lesions also were reduced to the greatest extent by the triple combination (61%), then clindamycin (50%). All 3 treatments were well-tolerated, although there were more adverse events in the triple combination group compared with the other groups. (Source, page S15)

tretinointretinoin_clind


Maintenance with Topical Retinoids

At this time, Adapalene is the most well-studied topical retinoid for maintance therapy once the acne has been considered “resolved.” This may be due to its reputation as one of the gentlest of the retinoids. In general though, retinoids are the preferred maintenance therapy due to their ability to prevent development of new acne lesions and resolve existing lesions quickly.

In a study on the efficacy of topical retinoids in the role of maintenance of acne, the following changes were observed:

retinoid_stopped

In a 16-week, randomized, vehicle-controlled maintenance study, patients who enrolled all originally were diagnosed with severe acne and only 28% of patients had moderate acne and 72% had mild or minimal acne or were clear at the time of the maintenance study. By the end of the study, more than 90% of patients were able to maintain their clearing while on adapalene maintenance therapy.

While the following graphs are a bit tough to read, they all should give you a general idea of the efficacy of retinoid maintenance therapies:

fig10fig11Fig9

The GAIOA concludes that maintenance therapy is an important tool for minimizing the likelihood of relapse, given the chronic nature of acne, with topical retinoids considered the best tool for this. They go on to state:

The majority of studies reported to date have lasted 3 to 4 months and show a trend toward continuing improvement with topical retinoid maintenance therapy and relapse when patients stop treatment. Clinical experience indicates that a longer duration of maintenance therapy is likely to be beneficial for many patients. Ongoing research will help to define the optimal duration of therapy and, perhaps, refine patient selection. Some patients with significant inflammation may need to be treated with a combination of retinoid and antimicrobial agent. This should be further studied.

The fact that microcomedones are subclinical and not apparent to the naked eye underscores the need to apply topical therapies to the entire affected area.
This, in turn, suggests that any agent used for maintenance therapy must be well tolerated. The current studies are well done and interesting; however, future studies should include comparison of several maintenance regimens in different patient populations.


Some Guidelines

Here are some things to conclude from this post:

  • Topical retinoids are very effective for treating acne, especially when used in combination with antimicrobials.
  • Prescription antimicrobials and retinoids need to be used on the entire effected area for efficacy and should not be used as spot treatments.
  • Adapalene is the most gentle of the retinoids.
  • Retinoid use should be maintained after treatment for acne has concluded.
  • Sunscreen should always be used with retinoids.
  • BPO should only be used with microsphere tretinoin, tazarotene, and adapalene.
  • Many generic forms of tretinoin are photo-unstable (break down in UV light) and should be used at night.

Sources

2 thoughts on “Skincare Ingredients: Tretinoin, Adapalene, and Tazarotene – part one

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  2. Pingback: Skinologist - The Mechanisms and Pathogenesis of Hormonal Acne (Acne Excoriée)

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