Exploring the Versatility of Topical Tretinoin
New findings question commonly held perceptions about tretinoin and suggest that, in the right formulation, the drug can be more patient-friendly than previously thought.
Tretinoin has been marketed for the topical treatment of acne vulgaris for nearly 40 years. During that time, it has been the subject of numerous in vitro and in vivo studies and incorporated into several different topical formulations. Despite its history of use and the volumes of data on it, clinicians continue to learn more about this first-generation retinoid. Increasingly, it appears that some of the common assumptions about tretinoin may be formulation dependent.
New Options in Combination Therapy
The long-standing admonition to avoid applying tretinoin and benzoyl peroxide concomitantly may not be well-founded. Tretinoin and the related compound isotretinoin are photodegraded by both visible light and UVR, with one investigation showing that tretinoin is most susceptible to the effects of UVA compared to other wavelengths. 1 This same investigation showed that vehicle composition could influence the rate of photodegradation of tretinoin, with different formulations showing different rates of degradation.
Tretinoin is also known to be degraded by benzoyl peroxide, with one study suggesting that the combination of benzoyl peroxide and light reduces tretinoin by 50 percent at two hours and 95 percent at 24 hours.2 Exposure to benzoyl peroxide in the absence of light also degraded tretinoin in this study.
Given that tretinoin and benzoyl peroxide have different and complementary actions in the management of acne (Table 1), they are frequently both prescribed for patients with mild to moderate acne vulgaris. Based on current acne treatment guidelines3 intended to reduce the risk of development of P. acnes resistance, patients with moderate to severe acne vulgaris treated with oral antibiotics should receive a prescription for benzoyl peroxide or benzoyl peroxide/clindamycin. If topical tretinoin is not also prescribed during the oral treatment phase—as it very well may be—it will quite likely be added in the maintenance phase, during which benzoyl peroxide will be continued.
Concerns about the stability of tretinoin have influenced the ways that clinicians build treatment regimens for their acne patients. Based on traditional concerns about photostability and the somewhat controversial issue of tretinoin-induced photosensitivity, 4 the topical retinoid is often prescribed for nighttime application. Since clinicians have sought to prevent co-administration of benzoyl peroxide with tretinoin, the antimicrobial is therefore prescribed for morning application. As such, the typical patient is now required to apply a medication each morning and evening, while the individual receiving systemic therapy has additional therapeutic duties. Evidence shows that patient adherence decreases as the number of daily drug applications increases. 5,6 The ability to simplify the regimen by having patients apply benzoyl peroxide concomitantly with tretinoin once each day could have a positive effect on patient adherence, and new data suggests that co-administration of certain formulations may be possible. 7
Tretinoin is inherently non-photostable, and benzoyl peroxide is a potent oxidizer. Yet it has been known for some time that features of the vehicle can enhance the stability of tretinoin in specific formulations.1 In a recent study, researchers showed that when benzoyl peroxide was mixed with a novel tretinoin gel 0.05% formulation (Atralin® Gel, Coria Laboratories), tretinoin was not degraded.7 For the in vitro study, tretinoin gel (0.05%) and benzoyl peroxide gel (6.26%) were combined. The benzoyl peroxide was a premix concentration used to produce 5% benzoyl peroxide in a fixed combination clindamycin product. The two gels were mixed at a one-to-one ratio in primary and duplicate samples that were maintained at 32°C, the temperature of human skin. At 1, 2, 3, 5, and 7 hours, each sample was assayed for percentage of tretinoin remaining and for degradation product content. After seven hours, 100 percent of the initial tretinoin concentration remained in the samples, indicating that benzoyl peroxide did not degrade tretinoin.
While the study did not investigate the effects in vivo of co-application of the two formulations, these findings suggest that the two agents can be used simultaneously without loss of efficacy of tretinoin. In fact, the authors note that real-world use by patients is less likely than the laboratory scenario to encourage degradation of tretinoin, because the two formulations would not be directly mixed. Instead, one formulation would be applied to the skin, leading to dilution of the active drug on the skin surface as it mixed with sebum and skin cells, before application of the second formulation.
Nighttime application of both topical agents may be advocated for many patients, assuming that it may be more convenient than morning applications, as individuals of all ages may be rushing to school, work, or appointments. Nightly application would also obviate any lingering concerns about UV's effect on tretinoin stability or skin irritancy.
Re-assessing Tolerability
Recent data also question assumptions about the irritancy of tretinoin and its suitability for use by adolescents. The pathogenesis of acne is directly tied to the hormonal changes that take place during adolescence. As such, the lower limit at which acne may develop is usually set at around age 10. At least anecdotally, some dermatologists say they encounter more patients developing acne in their pre-teen years.
Management of younger acne patients poses specific challenges, most notably in terms of compliance, which tends to be diminished in this age group.8,9 Given that the occurrence of side effects is also a significant contributor to poor compliance,9 prescribers should approach the management of younger acne patients with the goal of optimizing tolerability.
A study presented in poster (304) form at the recent Annual Meeting of the American Academy of Dermatology compared the cutaneous tolerability of tretinoin gel 0.05% and tretinoin microsphere gel 0.1% in a subpopulation of 983 adolescents ages 10 to 17 with mild to moderate acne. The study was a post-hoc analysis of pooled data from two multicenter double-blind studies that enrolled a total of 1,537 subjects with mild to moderate acne.
In both trials, subjects applied the assigned therapy once-daily for 12 weeks. The randomization method varied between the two studies. In the first study, subjects were randomized 2:2:1 to receive tretinoin gel 0.05%, tretinoin microsphere gel 0.1%, or vehicle. In the second study, subjects were randomized 1:1 to receive tretinoin gel 0.05% or vehicle.
Among patients treated with tretinoin gel 0.05%, 80 percent of adverse events (AEs) were mild and diminished within three weeks of therapy initiation. By contrast, 34 percent of AEs among patients treated with tretinoin microsphere gel 0.1% were moderate or severe. Whereas 29 percent of tretinoin 0.05% gel patients experienced treatment-related AEs, 54 percent of patients treated with tretinoin microsphere gel 0.1% did.
The cutaneous tolerability of tretinoin gel 0.05% was greater than that for tretinoin 0.1% microsphere in these studies. Fifty percent of subjects receiving tretinoin gel 0.05% reported one or more AEs, seven percent discontinued or interrupted therapy due to AEs, and one percent withdrew due to AEs, compared with 66 percent, 16 percent, and zero, respectively, for tretinoin microsphere gel 0.1%. Just one percent of subjects in each treatment group experienced a serious AE, and none were related to treatment.
The most commonly reported AEs in the tretinoin gel 0.05% group were dry skin (15 percent), followed by sensation of burning skin (eight percent), and erythema (six percent). The reported rates among tretinoin microsphere gel 0.01% patients were 32 percent for dryness, 14 percent for burning sensation, and 20 percent for erythema.
The good tolerability profile of tretinoin 0.05% gel along with the transient nature of AEs, which diminished within the first two to three weeks of treatment, led the authors to speculate that use of the formulation may improve patient adherence and treatment outcomes in the population of acne patients ages 10 to 17.
Patient-Focused Management
The ability to use tretinoin in combination with benzoyl peroxide allows patients to simplify their acne regimen, potentially contributing to improved adherence and therapeutic outcomes. Similarly, the enhanced tolerability of tretinoin gel 0.05% should also encourage adherence, especially in our youngest acne patients.
Just as clinicians continue to learn more about tretinoin, patients also need education. Consider that the parents of today's adolescent acne patient may very well have used the first-to-market tretinoin products, which were associated with significant irritation. These parents and their children should be informed about new directions in product formulation that have optimized the treatment experience.
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