I t’s difficult to imagine practicing dermatology without the availability of topical retinoids. Since 1971 when all-trans-retinoic acid, known more commonly as tretinoin (Retin-A), was released in the United States, we’ve been successfully treating acne and photoaging with topical retinoids, and we’ve been prescribing them for several “off-label” uses. Although retinol (all-trans-retinol) was the first of the available topical retinoids to be synthesized and investigated in the 1960s, the instability of this compound in previous formulations delayed its availability for commercial use. Subsequent scientific improvements in topical vehicles, utilizing sequestering polymers and antioxidants, resulted in prevention of retinol degradation. These important formulation modifications made it possible to manufacture topical products containing retinol with enhanced chemical stability and a prolonged product shelf life. As a result of these advances, retinol has been used in dermatologic products in the United States since 1984 and it continues to be a major tool in our arsenal of treatments. Here, we’ll review some of the latest applications and observations associated with topical retinoid therapy. Expanding The Armamentarium Newer Compounds. The armamentarium of the clinician was expanded by the release of two newer synthetic topical retinoids over the past 6 years in the United States. Released in 1996 with approval for acne therapy, adapalene (Differin) is a naphthoic acid derivative with retinoid activity found to produce less irritation and comparable efficacy when compared to tretinoin for the treatment of acne. Tazarotene (Tazorac), a retinoid exhibiting therapeutic properties that included antipsoriatic activity, was released in 1997 with initial approval for psoriasis, followed later by approval for acne treatment based on efficacy established in clinical trials. More recently, the cream formulation of tazarotene has undergone clinical investigation demonstrating efficacy for photoaging and is under formal evaluation for this indication. Newer Vehicles. Additional choices in topical retinoid therapy haven’t been limited to new compounds. Several additional vehicle formulations have been introduced. Tretinoin in an emollient cream base (Renova) was released and approved to treat photoaging in 1996. Also available were two vehicle modifications designed to reduce tretinoin-associated irritation, a microsponge gel (Retin-A Micro) and a polyoprepolymer-2 complex (Avita). Initially released as gel formulations only, tazarotene became available as both a 0.05% and 0.1% cream and adapalene as a 0.1% cream and solution. Experience with the cream formulations has resulted in high tolerability among patients with “dry” or sensitive skin types. This has been most applicable to tazarotene, as the gel formulation of this compound had proven to be irritating to many patients. Individual topical retinoid compounds and formulations may vary with regard to the specifics of their FDA-approved labeling and available product concentrations. The variety of vehicles (ie. cream, gel, solution, etc.) provides flexibility in accommodating different clinical presentations, skin types, application sites and individual patient tolerability. Continued research and clinical experience will undoubtedly provide additional useful information regarding optimal treatment protocols, methods to minimize irritation in susceptible patients, new clinical applications and comparative benefits. How Does Topical Retinol Fit In? Retinol has been available in multiple over-the-counter cosmetic products since 1984, leading to a perception among dermatologists that retinol use isn’t likely to provide significant therapeutic benefit for treatment of photoaging. Confusion regarding the therapeutic benefit of topically applied retinol is also related to limited understanding of the relationship between drug concentration and clinical response because retinol-containing products have been available in various concentrations. A resurgence of interest in topical retinol use has provided evidence supporting the therapeutic benefit of retinol in the treatment of photoaging. Whether or not the topical activity of retinol is related to its conversion to retinoic acid (tretinoin) has been a matter of debate due to conflicting laboratory findings. Retinol is converted in human skin principally to retinyl esters and small quantities of tretinoin. The inability in some analyses to detect tretinoin after application of retinol most likely relates to induction of retinoic acid-4 hydroxylase, an enzyme that exclusively metabolizes tretinoin. Induction of retinoic acid-4 hydroxylase activity appears to account for the lack of tretinoin accumulation in skin after application of retinol and likely explains why retinol has been shown in trials to require higher concentrations to induce epidermal changes comparable to tretinoin, with lesser irritation. Is Retinol Clinically Useful For PhotoAging? Available Studies. Clinical studies performed over usage periods of 3 months and 9 months have confirmed both the clinical (n = 24) and histologic benefits (n = 15) of retinol in managing photoaging. The trials included female patients with clinical evidence of photodamage with overall age ranges of 33 to 55 years. Histologic study evaluated changes in epidermal parameters of photoaging in forearm skin, such as epidermal thickness increase, keratinocyte orderliness and melanin decrease. At retinol concentrations of 0.3% and 0.6%, all patients exhibited significant epidermal changes, compared to only 40% of patients using 0.15% retinol. Photoaging Study. A recent comparative, investigator-blinded, split-face design study was performed to determine if hydroquinone 4%/retinol 0.3% cream (Alustra) applied twice daily was equivalent in efficacy to tretinoin 0.05% emollient cream (Renova) applied at bedtime in patients with Fitzpatrick skin phototypes I through IV, presenting with mild to moderate photodamage. An initial accommodation phase was used during the first 2 weeks with the hydroquinone 4%/retinol 0.3% cream applied daily and the tretinoin 0.05% emollient cream applied every other night. Sunscreen (SPF-15 rating) was utilized each morning and moisturizing cream was permitted if needed for facial dryness, with usage patterns logged by patients in a diary. The trial was completed in 41 Caucasian, Hispanic and Japanese female patients, evaluated for fine lines, coarse wrinkling, roughness, mottled pigmentation and melasma during 12 weeks of therapy. Clinical evaluations of efficacy for periocular fine lines, shallow wrinkles and roughness were assessed using a 10-point visual analog scale and overall global improvement of efficacy parameters. Evaluation of objective and subjective irritation parameters were assessed using a 4-point scale (none, mild, moderate or severe). Individual pigmentation parameters (ie. intensity, lesion size, location, homogeneity) were graded, with dyspigmentation evaluated using Melasma Area Severity Index (MASI) scores modified for split-face evaluation. Clinical improvement in melasma pigmentation correlates with reduction in MASI score values. In addition to investigator and patient assessments, photographic assessments were completed along with a regression phase analysis designed to evaluate the persistence of therapeutic benefit at 4 weeks after discontinuing drug application. All clinical and instrumentation data were compared to baseline for each visit and statistically analyzed (paired t-test). Both hydroquinone 4%/retinol 0.3% cream and tretinoin 0.05% emollient cream significantly reduced periocular fine lines (see table on page 51) and tactile roughness at weeks 4, 8 and 12 and periocular shallow wrinkles at week 12. The degree of benefit for these parameters were comparable for both agents during the treatment phase, with regression phase analysis demonstrating continuation of benefit at 4 weeks post-therapy with both agents. Overall pigmentation severity (see table above) and overall melasma severity (shown on the bar graph on page 59) were also reduced by both therapies, with hydroquinone 4%/retinol 0.3% cream demonstrating markedly superior improvement of individual and overall pigmentation parameters at weeks 4, 8 and 12 as compared to results achieved with tretinoin 0.05% emollient cream. The regression phase analysis indicated that continued significant improvement of individual and overall pigmentation parameters at 4 weeks post-therapy were demonstrated only for hydroquinone 4%/retinol 0.3% cream. Overall, both agents were very well tolerated with tretinoin 0.05% emollient cream demonstrating a greater tendency for dryness by week 8. PhotoAging Efficacy Triad. This study provides additional evidence supporting the value of topical retinol for treating photoaging, demonstrating efficacy comparable to tretinoin. There’s been a tendency to focus predominantly on fine lines, wrinkling and texture parameters as measures to evaluate the success of therapies for photoaging. As dyspigmentation is a significant component of the “photoaging complex,” research direction and therapeutic protocols are most efficacious when designed to decrease fine lines and wrinkles, improve texture and reduce pigmentation irregularities. By addressing all three components of the “efficacy triad,” the combined use of topical retinoid therapy with hydroquinone 4% enhances therapeutic benefit (see graphic on page 60). Value for Inflammatory Acne Lesions As dermatologists, we know that the primary lesion in the pathogenesis of acne is the microcomedone, a result of altered follicular epithelial cornification and abnormal desquamation. We’ve also long been aware that topical retinoids (tretinoin, adapalene, tazarotene) are effective comedolytic agents. The “disconnect” occurs when the clinician treats a patient with predominantly inflammatory acne and loses track of the concept that inflammatory acne lesions once began as microcomedones, and may only sometimes pass through a clinically evident comedonal phase. The presence of erythema related to inflammatory acne may also dissuade the clinician from utilizing a topical retinoid because of concern regarding irritation associated with topical retinoid therapy in some patients. In fact, all three of the available topical retinoids approved for acne have been shown in several studies to reduce development of both comedonal and inflammatory lesions. For example, adapalene 0.1% gel (Differin) and tretinoin 0.05% cream (Retin-A) produced comparable reductions in both non-inflammatory and inflammatory acne lesions in a 10-week trial using once daily application (n = 384). The median percentage reduction in non-inflammatory lesion counts exceeded 50% after 10 weeks, and inflammatory lesion counts decreased approximately 25% at 6 weeks and 40% at 10 weeks for both agents. Tazarotene 0.1% cream (Tazorac) applied once daily was shown in two 12-week trials (n = 424) to produce a median lesion count reduction ranging between 40% to 50% for both non-inflammatory and inflammatory lesions. This supports the paradigm that topical retinoid use is an important foundation therapy for long-term therapeutic success in the majority of patients treated for acne. Although topical retinoids exhibit no direct antimicrobial effects against Propionibacterium acnes, the progressive overall reduction in acne lesions over a usual time period of 2 to 4 months may allow for shorter durations of antibiotic therapy. This may indirectly result in a reduced need for more prolonged durations of antibiotic exposure with a subsequent decrease in emergence of antibiotic-resistant P. acnes strains. The use of benzoyl peroxide in patients undergoing antibiotic therapy for acne has also been shown to be favorable in reducing the proliferation and emergence of antibiotic-resistant P. acnes strains. It’s well established that topical retinoid therapy for acne is very effective when used appropriately, and in conjunction with other topical agents that direct their action primarily against the inflammatory component of acne pathogenesis. Examples include benzoyl peroxide (Triaz, Benzac, Brevoxyl, others), topical clindamycin phosphate 1% (Clindagel, Cleocin T), topical erythromycin 2% (ATS, Akne-mycin, others), sulfacetamide 10%/sulfur 5% suspension (Plexion TS) or lotion (Sulfacet), azelaic acid 20% cream (Azelex, Finevin) and topical benzoyl peroxide/antibiotic formulations (Benzaclin, Benzamycin). Use of sulfacetamide 10%/sulfur 5% may also provide additional comedolytic activity, further enhancing the effect produced by topical retinoid treatment. It’s usually recommended that the topical retinoid be applied prior to bedtime and the other topical agents are generally applied earlier in the day. When applicable, based on disease severity, systemic antibiotic therapy may be used in conjunction with the topical therapy protocol. Avoidance of Irritation Irritation can sometimes be a problem, but with a better understanding of how topical retinoid therapy may be initiated, and with improved vehicle selections, one can usually reduce the risk of significant irritation that is sometimes encountered. The “irritation reputation” associated with topical retinoid therapy was initially propagated after the introduction of tretinoin due to early-on use of high concentrations and highly irritating solution and gel formulations. As mentioned earlier, the initial release of tazarotene in a gel formulation also proved to be too irritating for many patients. Although the gel formulations of tretinoin and tazarotene are still applicable to certain patient types, the availability of other vehicle options and strengths has resulted in greater flexibility and lower irritancy when using these agents. Fortunately, we have reached a time where the majority of acne patients can utilize topical retinoid therapy with little or no adverse consequence. There are some patients who are exquisitely “retinoid sensitive” and quickly develop signs and symptoms of irritation — fortunately they are the exception. Progressive Application Techniques. Another subset exhibits “cumulative irritancy,” a presentation that can often be overcome by slower initiation of therapy, progressive application frequency, appropriate vehicle selection and proper cleansing and moisturizer use. It must be appreciated that when combination topical therapies are used, other agents also carry with them their own irritancy potential. An approach that is often helpful in reducing irritation with topical acne treatment is to initiate nighttime application of topical retinoid therapy every other night for the first week, and then nightly for the second week. At this point, if no significant irritation remains, then add to the regimen the recommended morning and/or daytime applications of other prescribed topical agents, such as benzoyl peroxide, topical antibiotic therapy, etc. This progressive “go slow” approach: • allows a period of accommodation to the topical retinoid and other products. • facilitates identification of the component of the therapeutic protocol that was the “culprit” in initiating significant irritation should it develop. If a topical retinoid is being added to a topical acne regimen that’s already in progress and that’s not associated with significant irritation, start the topical retinoid in the same progressive fashion at bedtime. Continue having the patient use established products he or she has been using (i.e. benzoyl peroxide, topical antibiotic, etc.) earlier during the day. Benzoyl Peroxide Wash plus Topical Retinoid: Does It Work? Withstanding the “test of time” over decades of use, benzoyl peroxide has continued to be a “workhorse” of acne therapy because of its marked ability to reduce inflammatory lesions, potentiate the effect of antibiotic therapy and reduce emergence of antibiotic-resistant P. acnes strains. Resistance of P. acnes to benzoyl peroxide has not been identified, likely related to a direct toxic mechanism of action. As monotherapy, benzoyl peroxide applied twice daily as a “leave-on” gel product over 6 weeks produces a 2-fold log reduction in P. acnes colony-forming units. The use of benzoyl peroxide 10% gel (Triaz) applied twice daily and oral minocycline (Dynacin) 100 mg twice daily over 6 weeks resulted in additive P. acnes suppression. Oral minocycline alone reduces P. acnes colony-forming units at a log reduction value of 2 to 2.5; combination of minocycline with benzoyl peroxide resulted in a log reduction value of 4. By week 6, P. acnes organism growth was negligible as compared to baseline. Benzoyl peroxide gels can be drying or irritating to some patients and may bleach colored fabric if not thoroughly applied and absorbed into the skin (ie. back area). So benzoyl peroxide wash may serve as a viable alternative or addition to “leave-on” gel use if a therapeutic effect can be achieved with the shorter contact time. Combination Study. In a 12-week, controlled, investigator-blinded study of male (n = 22) and female (n = 34) patients with moderate facial inflammatory acne, the combination of benzoyl peroxide 6% cleanser (Triaz) in the morning and tretinoin 0.1% microsphere gel (Retin-A Micro) in the evening (n = 30) was compared to evening application with tretinoin 0.1% microsphere gel alone (n = 26). The goals of the study were to evaluate efficacy and tolerability of both regimens. Both groups were given a gentle cleanser (Cetaphil Liquid Cleanser) to use in morning and evening, except during the morning for those patients using the benzoyl peroxide 6% cleanser. A non-comedogenic sunscreen (Neutrogena Moisture SPF 15) was provided for all patients to apply in the morning approximately 5 minutes after facial cleansing, with additional use as needed throughout the day. The age range of enrolled subjects was 12 to 30 years, including Fitzpatrick skin phototypes I through V. Patients were followed at weeks 2, 6 and 12. Evaluation indices included inflammatory (papules, pustules) and non-inflammatory (comedonal) lesion counts, acne severity, severity of acne-associated erythema and conventional parameters of irritation (ie. dryness, scaling, erythema, peeling). By endpoint at week 12, patients using the combination protocol of benzoyl peroxide 6% gel (Triaz) and tretinoin 0.1% microsphere gel (Retin-A Micro) demonstrated: • 58.5% reduction in inflammatory lesions • 44.1% reduction in non-inflammatory lesions • 54.5% reduction in overall acne severity based on lesion counts • 47.5% reduction in acne-associated erythema. The group treated with tretinoin 0.1 % microsphere gel alone exhibited: • 29.8 % reduction in inflammatory lesions • 48.9 % reduction in non-inflammatory lesions • 30.7 % reduction in overall acne severity • 18.2 % reduction in acne-associated erythema. Other than reduction in non-inflammatory lesions, which was comparable in both treatment arms, the combination treatment regimen proved to be statistically superior to the use of tretinoin 0.1% microsphere gel alone (without morning use of benzoyl peroxide 6% cleanser). The low number of patients experiencing significant irritation was comparable in both treatment groups, with no dropouts in either study arm as a result of adverse events related to drug usage. This study supports the value of benzoyl peroxide cleanser in enhancing therapy of acne by reducing inflammatory acne lesions and decreasing acne-related erythema. Use of the benzoyl peroxide cleanser did not interfere with the activity or efficacy of topical retinoid therapy and was not associated with a significant increase in irritation. BackBone of Therapy Patients and physicians continue to benefit from continued research on retinoids, including development of newer topical agents, improvements in vehicles and additional clinical studies, which outline treatment protocols and new clinical applications. With appropriate usage of specific agents, coupled with adjustments in therapy based on patient response, topical retinoids continue to maintain their position as a “backbone” of therapy for acne and photoaging. Some agents may also offer unique therapeutic benefits for specific disease states such as psoriasis. Over time, additional clinically useful information on topical retinoids is sure to unfold.