170
171
Benzoyl peroxide
Salicylic acid
Combinations
Inflammatory
Noninflammatory
an undetectable film of medication remains on the skin subsequent to rinse-off. Systemic absorption of topical products
increases with increased surface area of contact, application
to a disrupted skin barrier, duration, and frequency of application.6
Benzoyl Peroxide
products are recommended, dermatologists must be capable
of explaining why these products are superior to OTC alternatives. Finally, a physician should be able to advise which
OTC products must be discontinued during therapy while
recognizing which products best complement the prescribed
therapeutic regimen.
OTC therapies might be more cosmetically elegant, accessible, strategically advertised, less expensive, and less irritating than prescription therapies. However, the question remainsjust how effective are these products? The purpose of
this review is to discuss the efficacy of currently available
OTC acne treatments and to introduce some potential future
OTC acne therapies in development.
General Principles
OTC drugs may be sold without a prescription and without a
visit to a medical professional. In the United States, the manufacture and sale of OTC substances is regulated by the Food
and Drug Administration (FDA). In order for a drug to be
sold OTC, it must primarily be used to treat a condition that
does not require the direct supervision of a physician and
must be proven to be reasonably safe and well-tolerated, with
little or no abuse potential. Over time, drugs that prove themselves safe and appropriate for self-medication may be
switched from prescription to OTC.
Most dermatological OTC products are designed for topical application. One clear advantage of topical preparations is
local application to the affected area, thereby maximizing
exposure to the pilosebaceous units while minimizing systemic absorption (Table 2). However, if the drug is formulated such that it cannot penetrate the pilosebaceous unit
(secondary to molecular size or hydrophylicity), the active
ingredient will merely sit on the skin surface without ever
reaching its target. In this case, these drugs may have impressive in vitro study results that may never translate to clinical
efficacy.
OTC topical products come in a variety of strengths and
formulations. As with topical prescription products, formulations include gels, pledgets, washes, solutions, lotions, and
creams. Creams and lotions are preferable for patients with
dry, easily irritated skin,5 whereas the other formulations can
be drying and are particularly suited for oily skin.
The main side effect of topical products is irritation. Dermatologists frequently discourage patients from applying
anything to their faces other than what is prescribed so as to
minimize irritation.5 Increased irritation will result from
more liberal or more frequent application of a drug. Cleansers and masks are washed off after transient application.
However, some washes demonstrate substantivity, meaning
172
erythema caused by BPO, prescription 2.5% BPO might be
more suitable, offering an equally effective but less irritating
alternative.
Irritation is the most common side effect experienced with
BPO use. This irritation may take the form of erythema, dryness, peeling, stinging, or burning. This discomfort will increase with increasing concentration and frequency of use.
Contact sensitization, however, may occur in up to 2.5% of
patients,19 and will occur with any concentration as soon as
the patient is sensitized.
Vehicles may also be important in influencing the efficacy
and side effects of BPO. Some OTC BPO products claim that
the vehicle in which the BPO is delivered significantly enhances compliance by creating a cosmetically elegant product that also minimizes irritation (Proactiv, or the prescription BPO, Brevoxyl [Stiefel]). BPO is a Pregnancy Category C
drug. Although it is not specifically FDA approved for pediatric use, its OTC status makes such use inevitable.
Salicylic Acid
Salicylic acid (SA; from Salix, the Latin word for the willow
tree) is a phytohormone, a plant product that acts like a
hormone by regulating cell growth and differentiation. It is a
beta hydroxy acid that is chemically similar to the active
component of aspirin. It functions as a topical desquamating
agent, dissolving the intercellular cement holding the cells of
the stratum corneum together.20 Because SA is also lipid soluble (unlike alpha hydroxy acids), it is able to penetrate the
pilosebaceous unit and have a comedolytic effect. Although
SA has been used for many years in the treatment of acne and
is found in a variety of OTC acne remedies (particularly
cleansers), few well-designed clinical trials of its safety and
efficacy exist. It is considered moderately effective in the
treatment of acne,21 and its comedolytic properties are considered less potent than topical retinoids. Therefore, SA is
used by dermatologists when patients cannot tolerate topical
retinoid, or benzoyl peroxide therapy because of skin irritation,22,23 or as adjunctive therapy to other, more effective,
medications.
Concentrations of SA ranging from 0.5% to 10% have been
used for the treatment of acne,24,25 but concentrations of 3%
to 6% are more commonly reserved for hyperkeratotic skin
disorders (eg, psoriasis, ichthyoses, keratosis pilaris, etc)26
and 5% to 40% concentrations are used for wart and corn
removal. The maximum strength of SA permitted in OTC
acne products in the United States is 2%. SA is an FDA
Pregnancy Category C drug, and the safety of SA consumption by nursing mothers is unknown. It is, however, approved for use in pediatric acne.
Although SA is generally considered to be a less-potent
agent in the treatment of acne when compared with BPO, at
least 2 studies contradict this assumption. In a study submitted to the FDA in 1982, one of us (ARS) demonstrated the
superiority of 2% SA alcoholic detergent solution (Stridex) as
compared with BP 5% cream.27 It was later found that patients treated with a 2% SA cleanser for 2 weeks showed a
significant improvement in acne but worsened when using a
Sulfur
The chemical element sulfur has been used to treat acne for
decades. It is a yellow, nonmetallic element with mild keratolytic, antifungal and bacteriostatic properties.39,40 Its precise mechanism of action is unknown. When in contact with
keratinocytes, sulfur is thought to interact with cysteine in
the stratum corneum, thereby reducing sulfur to hydrogen
sulfide.41 Hydrogen sulfide is then capable of degrading keratin, hence the keratolytic activity of sulfur. The smaller the
particle size of sulfur, the more interaction that can occur
with keratin and, hence, the greater the efficacy.41 Sulfur is
found in OTC and prescription topical acne products, with
concentrations ranging from 1 to 10%. It may be found in
lotions, creams, soaps and ointments.
Efficacy appears to increase when sulfur is combined
with benzoyl peroxide42,43 and sodium sulfacetamide,44
and sulfur is also found in combination with resorcinol or
salicylic acid. One study showed that sulfur was comedogenic when applied to human and rabbit skin,45 but contrary results have been found in a subsequent doubleblind, randomized study.46,47 Side effects are rare, mainly
limited to malodor and dry skin.41 Although older sulfurcontaining formulations were effective, their application
was time consuming, messy, and they were associated
with an unpleasant odor (eg, Vleminckx solution, Ress
Sodium Sulfacetamide
Sodium sulfacetamide is a sulfonamide capable of inhibiting
P. acnes proliferation. Sulfonamides act through competitive
antagonism of para-aminobenzoic acid, halting bacterial
DNA synthesis. A 10% concentration of sodium sulfacetamide is commonly combined with 5% sulfur in topical acne
suspensions, lotions, cleansers, and creams. This combination has been shown to reduce both inflammatory lesions and
comedones.44,50 It also appears to be cosmetically appealing,
showing only mild transient dryness and itching44,50 as well
as synergistic.51
Percutaneous absorption through human cadaver skin is
estimated at 4%.39,50 Adverse reactions are infrequent and
usually restricted to pruritus or erythema at the application
site. Generally, sodium sulfacetamide is considered less irritating than benzoyl peroxide and retinoic acid.50,52 Rare
cases of erythema multiforme53 and StevensJohnson syndrome50,54,55 have been reported after topical ophthalmic use.
Topical sodium sulfacetamide is contraindicated in patients
with a sulfa allergy, as hypersensitivity can occur following
re-administrations of sulfa by any route.49,55 Sodium sulfacetamide is also avoided in patients with a sulfonamide allergy, as sulfa and sulfonamides are thought to cross-react.
173
and re-epithelization process.61 There appears to be a synergistic lightening effect when these 2 agents are combined.
Zinc
Zinc is a metallic chemical element that is crucial for the
normal development and physiology of human skin.62 Approximately 6% of total body zinc is found in the skin.63 In
the 1970s, Fitzherbert64 first reported improvement of acne
on oral zinc supplementation of zinc in zinc-deficient patients. Serum zinc levels in patients with acne were found to
be low,65,66 and oral zinc was subsequently reported to be
effective in the treatment of severe and inflammatory
acne,67-73 moreso than mild or moderate acne.74,75 Zinc is
bacteriostatic against P. acnes, inhibits chemotaxis, and may
decrease tumor necrosis factor- production. Despite these
promising effects, oral doses used in these studies (200 mg of
zinc gluconate per day, 400 or 600 mg of zinc sulfate per
day) were associated with nausea, vomiting, and diarrhea.13,69,70,73,75 Gastrointestinal side effects can be ameliorated somewhat by ingesting zinc directly after meals. One to
two milligrams of copper supplementation may be recommended with long-term zinc therapy to prevent copper deficiency, because zinc decreases the absorption of copper. Oral
zinc salt supplementation has been shown to be equally or
less effective than oral tetracyclines.68,76-83 One study, however, showed that oral zinc sulfate had no effect on male
patients with moderate acne after 8 weeks of therapy, despite
evidence of systemic absorption.74 Limited efficacy and poor
patient compliance caused by gastrointestinal side effects
limit the use of oral zinc for the treatment of acne. Further
trials need to be conducted to assess the efficacy and side
effects of lower doses of oral zinc.
Vitamin A
The naturally occurring form of vitamin A is also known as
retinol. Retinol is transformed into numerous metabolites,
including retinoic acid (aka tretinoin, the active ingredient in
Retin-A, Tretin-X, and others). It is widely used in toiletries
and cosmetics as a GRAS (ie, generally recognized as safe)
ingredient. Most OTC retinol products contain between
0.04% and 0.07% retinol.
Theoretically, topical retinol should have a similar mechanism of action as its metabolite, tretinoin, in the treatment of
acne.Unlike tretinoin, retinol oxidizes very rapidly and is
inactivated by ultraviolet light. Thus, OTC preparations containing retinol may demonstrate a wide range of activity.
Some delivery systems have been developed to enhance the
stability and topical absorption of the molecule. Topical retinol is primarily touted to diminish the appearance of fine
lines and wrinkles, and even skin tone. Although often considered beneficial in the treatment of acne, there are no published, peer-reviewed clinical studies demonstrating antiacne
effects. Oral vitamin A (retinol) has been shown to benefit
acne when used in high doses (300,000 units daily for
women, 400,000 to 500,000 units daily for men).84 Adverse
events were limited to xerosis and cheilitis.
174
Ayurvedic Therapies
In Sanskrit, ayu means life, and veda means knowledge.
Ayurveda is a 5000-year-old history Indian traditional system of medicine. Two randomized, double-blind, placebocontrolled trials were undertaken to study the effect of oral,86
and oral/topical combination,87 preparations of Ayurvedic
herbal extracts on acne. In the first study, treatment with an
oral preparation of Sunder Vati resulted in a significant reduction in lesion count and was well tolerated.88 Treatment
with the 3 other oral formulations studied failed to show any
improvement. The second study demonstrated that the combination of an oral Ayurvedic preparation and a topical
Ayurvedic, multicomponent preparation (cream or gel) was
more efficacious in treating acne than oral therapy alone.89
The topical cream showed more efficacy when combined
with the oral tablet than did the topical gel.
Other Therapies
There is no convincing evidence to support the use of vitamin
B6 (pyridoxine),90 chromium,91 or selenium92 in the treatment of acne. Several natural ingredients possess antioxidant,
antiinflammatory, and/or moisturizing properties which may
be useful additions to, or vehicles for, more effective acne
therapies. These include colloidal oatmeal, feverfew, licorice,
aloe vera, chamomile, curcumin, soy, coffeeberry, mushroom extracts, green tea, pine bark extract, vitamin E, vitamin C, and niacinamide.93-100 There is no evidence that these
natural ingredients possess any antiacne activity per se. However, their soothing, antiinflammatory effects could theoretically assist in decreasing the erythema associated with inflammatory acne, and their moisturizing properties could
potentially counter some of the drying effects produced by
more potent acne therapies.
Conclusion
In conclusion, although acne is ubiquitous, only a fraction of
acne sufferers are treated by physicians with prescription
products. There is, however, a large and expanding market
for OTC medications, many of which are not only effective
but also well tolerated and cosmetically elegant. OTC acne
systems or kits have recently gained popularity and appear
to have increased patient compliance. BPO and SA are the
most common ingredients in OTC acne products. Other, less
common OTC ingredients include sulfur, sodium sulfacetamide, and AHAs. Oral zinc, retinol, oral vitamin A, tea tree
oil, and ayurvedic therapies are also available OTC for acne.
Additional and better studies are needed to clarify the benefit
of these latter medications.
To review, SA shows moderate activity against both inflammatory and noninflammatory lesions. A combination of
these 2 therapies, however, is a very effective treatment for
both inflammatory and noninflammatory lesions. BPO is
generally considered to be the most effective OTC ingredient
for reducing inflammatory lesions, and it shows moderate
activity against noninflammatory lesions. BPO and SA are the
2 most common ingredients found in OTC acne therapies.
Less commonly, sulfur, sodium sulfacetamide, and AHAs are
also found in OTC acne products.
References
1. Kraning KK, Odland GF: Prevalence, morbidity and cost of dermatologic diseases. J Invest Dermatol 73:395-401, 1979 (suppl)
2. Collier CN, Harper JC, Cantrell WC, et al: The prevalence of acne in
adults 20 years and older. J Am Acad Dermatol 58:56-59, 2008
175
30. Schwarb FP, Gabard B, Rufli T, et al: Percutaneous absorption of
salicylic acid in man after topical administration of three different
formulations. Dermatology 198:44-51, 1999
31. Pertoldi F, DOrlando L, Mercante WP: Acute salicylate intoxication
after trancutaneous absorption. Minerva Anestesiol 65:571-573, 1999
32. Raschke R, Arnold-Capell PA, Richeson R, et al: Refractory hypoglycemia secondary to topical salicylate intoxication. Arch Intern Med
151:591-593, 1991
33. Candy JM, Morrison C, Paton RD, et al: Salicylate toxicity masquerading as malignant hyperthermia. Paediatr Anaesth 8:421-423, 1998
34. Chiaretti A, Schembri WD, Tortorolo L, et al: Salicylate intoxication
using a skin ointment. Acta Paediatr 86:330-331, 1997
35. Davies MG, Briffa DV, Greaves MW: Systemic toxicity from topically
applied salicylic acid. BMJ 1:661, 1979
36. Germann R, Schindera I, Kuch M, et al: Life threatening salicylate
poisoning caused by percutaneous absorption in severe ichthyosis
vulgaris. Hautarzt 47:624-627, 1996
37. Pec J, Strmenova M, Palencarova E, et al: Salicylate intoxication after
use of topical salicylic acid ointment by a patient with psoriasis. Cutis
50:307-309, 1992
38. Poe TE, Scott RB, Keith JF Jr: Drug interactions with furosemide.
J Fam Pract 18:204, 1984
39. Physicians Desk Reference. Montvale, NJ, Medical Economics Company Inc., 2002
40. Gupta AK, Nicol K: The use of sulfur in dermatology. J Drugs Dermatol 3:427-431, 2004
41. Lin AN, Reimer RJ, Carter DM: Sulfur revisited. J Am Acad Dermatol
18:553-558, 1988
42. Danto JL, Maddin WS, Stewart WD, et al: A controlled trial of benzoyl
peroxide and precipitated sulfur cream in acne vulgaris. Appl Ther
8:624-625, 1966
43. Wilkinson RD, Adam JE, Murray JJ, et al: Benzoyl peroxide and sulfur:
Foundation for acne management. Can Med Assoc J 95:28-29, 1966
44. Breneman DL, Ariano MC: Successful treatment of acne vulgaris in
women with a new topical sodium sulfacetamide/sulfur lotion. Int J
Dermatol 32:365-367, 1993
45. Mills OH Jr., Kligman AM: Is sulphur helpful or harmful in acne
vulgaris? Br J Dermatol 86:620-627, 1972
46. Fulton JE Jr., Pay SR, Fulton JE III: Comedogenicity of current therapeutic products, cosmetics, and ingredients in the rabbit ear. J Am
Acad Dermatol 10:96-105, 1984
47. Strauss JS, Goldman PH, Nacht S, et al: A reexamination of the potential comedogenicity of sulfur. Arch Dermatol 114:1340-1342, 1978
48. Kaminsky A: Less common methods to treat acne. Dermatology 206:
68-73, 2003
49. Akhavan A, Bershad S: Topical acne drugs: Review of clinical properties,
systemic exposure, and safety. Am J Clin Dermatol 4:473-492, 2003
50. Tarimci N, Sener S, Kilinc T: Topical sodium sulfacetamide/sulfur
lotion. J Clin Pharm Ther 22:301, 1997
51. Olansky S: Old drugin a new systemrevisited. Cutis 19:852-854,
1977
52. Olansky S: Old drugin a new systemrevisited. Cutis 19:852-854,
1977
53. Genvert GI, Cohen EJ, Donnenfeld ED, et al: Erythema multiforme
after use of topical sulfacetamide. Am J Ophthalmol 99:465-468,
1985
54. Gottschalk HR, Stone OJ: Stevens-Johnson syndrome from ophthalmic sulfonamide. Arch Dermatol 112:513-514, 1976
55. Rubin Z: Ophthalmic sulfonamide-induced Stevens-Johnson syndrome. Arch Dermatol 113:235-236, 1977
56. Van Scott EJ, Yu RJ: Hyperkeratinization, corneocyte cohesion, and
alpha hydroxy acids. J Am Acad Dermatol 11:867-879, 1984
57. Tung RC, Bergfeld WF, Vidimos AT, et al: Alpha-hydroxy acid-based
cosmetic procedures. Guidelines for patient management. Am J Clin
Dermatol 1:81-88, 2000
58. Dreno B, Nocera T, Verriere F, et al: Topical retinaldehyde with glycolic acid: Study of tolerance and acceptability in association with
anti-acne treatments in 1,709 patients. Dermatology 210:22-29, 2005
(suppl 1)
176
59. Poli F, Ribet V, Lauze C, et al: Efficacy and safety of 0.1% retinaldehyde/6% glycolic acid (diacneal) for mild to moderate acne vulgaris. A
multicentre, double-blind, randomized, vehicle-controlled trial. Dermatology 210:14-21, 2005 (suppl 1)
60. Tran C, Kasraee B, Grand D, et al: Pharmacology of RALGA, a mixture
of retinaldehyde and glycolic acid. Dermatology 210:6-13, 2005
(suppl 1)
61. Katsambas AD: RALGA (Diacneal), a retinaldehyde and glycolic acid
association and postinflammatory hyperpigmentation in acnea review. Dermatology 210:39-45, 2005 (suppl 1)
62. Prasad AS: Zinc deficiency. BMJ 326:409-410, 2003
63. King JC, Shames DM, Woodhouse LR: Zinc homeostasis in humans.
J Nutr 130:1360S-1366S, 2000
64. Fitzherbert JC: Zinc deficiency in acne vulgaris. Med J Aust 2:685686, 1977
65. Amer M, Bahgat MR, Tosson Z, et al: Serum zinc in acne vulgaris. Int
J Dermatol 21:481-484, 1982
66. Michaelsson G, Vahlquist A, Juhlin L: Serum zinc and retinol-binding
protein in acne. Br J Dermatol 96:283-286, 1977
67. Dreno B, Amblard P, Agache P, et al: Low doses of zinc gluconate for
inflammatory acne. Acta Derm Venereol 69:541-543, 1989
68. Dreno B, Moyse D, Alirezai M, et al: Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of
zinc gluconate versus minocycline hydrochloride in the treatment of
inflammatory acne vulgaris. Dermatology 203:135-140, 2001
69. Goransson K, Liden S, Odsell L: Oral zinc in acne vulgaris: A clinical
and methodological study. Acta Derm Venereol 58:443-448, 1978
70. Hillstrom L, Pettersson L, Hellbe L, et al: Comparison of oral treatment with zinc sulphate and placebo in acne vulgaris. Br J Dermatol
97:681-684, 1977
71. Liden S, Goransson K, Odsell L: Clinical evaluation in acne. Acta
Derm Venereol Suppl (Stockh) 89:47-52, 1980
72. Michaelsson G, Juhlin L, Vahlquist A: Effects of oral zinc and vitamin
A in acne. Arch Dermatol 113:31-36, 1977
73. Verma KC, Saini AS, Dhamija SK: Oral zinc sulphate therapy in acne
vulgaris: A double-blind trial. Acta Derm Venereol 60:337-340, 1980
74. Orris L, Shalita AR, Sibulkin D, et al: Oral zinc therapy of acne.
Absorption and clinical effect. Arch Dermatol 114:1018-1020, 1978
75. Weimar VM, Puhl SC, Smith WH, et al: Zinc sulfate in acne vulgaris.
Arch Dermatol 114:1776-1778, 1978
76. Cunliffe WJ: Unacceptable side-effects of oral zinc sulphate in the
treatment of acne vulgaris. Br J Dermatol 101:363, 1979
77. Michaelsson G, Juhlin L, Ljunghall K: A double-blind study of the
effect of zinc and oxytetracycline in acne vulgaris. Br J Dermatol 97:
561-566, 1977
78. Feucht CL, Allen BS, Chalker DK, et al: Topical erythromycin with
zinc in acne. A double-blind controlled study. J Am Acad Dermatol
3:483-491, 1980
79. Habbema L, Koopmans B, Menke HE, et al: A 4% erythromycin and
zinc combination (Zineryt) versus 2% erythromycin (Eryderm) in
acne vulgaris: A randomized, double-blind comparative study. Br J
Dermatol 121:497-502, 1989
80. Schachner L, Eaglstein W, Kittles C, et al: Topical erythromycin and
zinc therapy for acne. J Am Acad Dermatol 22:253-260, 1990
81. Schachner L, Pestana A, Kittles C: A clinical trial comparing the safety
and efficacy of a topical erythromycin-zinc formulation with a topical
clindamycin formulation. J Am Acad Dermatol 22:489-495, 1990
82. Van Hoogdalem EJ, Terpstra IJ, Baven AL: Evaluation of the effect of
zinc acetate on the stratum corneum penetration kinetics of erythromycin in healthy male volunteers. Skin Pharmacol 9:104-110, 1996
83. Cochran RJ, Tucker SB, Flannigan SA: Topical zinc therapy for acne
vulgaris. Int J Dermatol 24:188-190, 1985