Journal of the Dermatology Nurses' Association:
Dapsone in the Management of Acne Vulgaris
Radley, Kathy; Tucker, Rod
Kathy Radley, BSc (hons), RGN, Faculty of Health and Social Care, University of Hull, Hull, United Kingdom, and Department of Dermatology, Pilgrim Hospital, Lincolnshire, United Kingdom.
Rod Tucker, BPharm, PhD, Faculty of Health and Social Care, University of Hull, Hull, United Kingdom.
The authors have no funding in relation to this article and no other declarations of interest. The manuscript has not been submitted nor will be submitted for any other publication.
The authors declare no conflicts of interest.
Correspondence concerning this article should be addressed to Kathy Radley, BSc (hons), RGN, Faculty of Health and Social Care, University of Hull, Cottingham Rd, Hull, Yorkshire HU6 7RX, United Kingdom. E-mail: firstname.lastname@example.org
Dapsone has had a long history of use in medicine dating back to the 1930s although the compound was originally discovered in 1908. The drug has been successfully deployed in the treatment of a range of conditions including leprosy, malaria, dermatitis herpetiformis, tuberculosis, and opportunistic infections such as pneumocystis pneumonia in patients with human immunodeficiency virus. Dapsone possesses both antibacterial and anti-inflammatory properties, and this dual action was utilized in the management of moderate to severe acne. However, the adverse effect profile of the drug limited its usefulness as an anti-acne therapy, and Dapsone use was superseded by isotretinoin during the 1980s. Dapsone was resurrected as an acne therapy in 2008 after the introduction of Aczone, a topical formulation of the drug with fewer side effects and was deemed suitable for patients with mild-to-moderate disease. Aczone is currently only available in the United States and Canada. Although clinical studies suggest that the drug is effective, the lack of comparative studies with established therapies makes the position of Aczone in the management of acne more difficult to define.
Dapsone is an antibacterial agent that also possesses anti-inflammatory properties and is used extensively in dermatology, predominately for inflammatory dermatoses. A topical formulation of the drug has recently been introduced for the management of acne vulgaris.
Dapsone was first synthesized in 1908 by German chemists in the dye industry, but its potential medicinal use was not realized until the 1930s when there was great interest in the recently discovered sulfonamides, a class of sulfur-containing molecules, which were the first broad-spectrum antimicrobial agents. Researchers were keen to find other chemically similar agents to add to this new class, and in 1937, dapsone (which is a sulfone and chemically similar to sulfonamides) was successfully used to treat experimentally induced streptococcal infections in mice (Zhu & Stiller, 2001). Other animal research confirmed the superior efficacy of dapsone (compared with sulfonamides) against streptococcal infections but also identified that dapsone was more toxic, inducing a wide range of side effects including anemia and methemoglobinemia (Barr, 2011).
In 1941, dapsone was shown to be effective in animal studies against tuberculosis and leprosy (Sago & Hall, 2002), and in 1949, an oral formulation was used in the treatment of leprosy. The following year, sulfones were given to patients with dermatitis herpetiformis based on the (incorrect) assumption that the condition had an infective cause (Wolf, Tuzun, & Tuzun, 2000). The patients’ conditions improved, and subsequent work confirmed these initial findings. Today, dapsone is licensed for the use of dermatitis herpetiformis and also in the management of a range of noninfective inflammatory, bullous, and auto-immune diseases (Gordon, Mays, Sambrano, Mayo, & Lapolla, 2012). The first published study of dapsone in the management of acne was a placebo controlled trial (Ross, 1961), which showed a great improvement in 9 of 23 patients, although nine showed no improvement. A later study (Prendiville, Logan, & Russel-Jones, 1988) compared dapsone and 13-cis-retinoic acid (isotretinoin), although the benefits of dapsone were described as marginal. The introduction of isotretinoin during the 1980s replaced virtually all other treatments for the more severe forms of acne. Dapsone still appears to have a potential role in the management of a severe and rare form of acne, acne fulminans with erythema nodosum (Tan, Lear, & Smith, 1997), although it has been suggested that, when used alone, the drug may be of limited value in acne fulminans (Zaba, Schwartz, Jarmuda, Czarnecka-Operacz, & Silny, 2011). The potential side effects of dapsone (see below for adverse effects) have restricted the use of the drug as an oral therapy for acne. A topical formulation of the drug has been recently introduced in an attempt to maximize the benefits while minimizing the adverse effects.
MECHANISM OF ACTION
The antibacterial action of dapsone, as with sulfonamides, is through competitive inhibition of the enzyme necessary for the synthesis of folic acid, which is ultimately incorporated into bacterial deoxyribonucleic acid. Sulfones such as dapsone and sulfonamides are therefore bacteriostatic (stopping cellular growth) rather than bactericidal (killing microorganisms). The bacteriostatic activity of dapsone against propionibacterium acnes (P. acnes) is low and comparable with vehicle (placebo; Center for Drug Evaluation and Research, 2005), indicating that the anti-inflammatory effects of dapsone are more relevant in acne. The precise mechanism of action remains unclear. Some evidence suggests that inflammation is key to the initiation of acne lesions (Jeremy, Holland, Roberts, Thompson, & Cunliffe, 2003), and dapsone appears to inhibit chemo-attractant signaling that prevents neutrophil recruitment at the site of inflammation (Debol, Herron, & Nelson, 1997). Dapsone also inhibits the myeloperoxidase enzyme system in neutrophils, which produce reactive oxygen species that not only kill microorganisms but also cause tissue damage and inflammation (Wozel & Barth, 1988). There is also evidence that dapsone affects other inflammatory systems (Wozel, 2010) and the drug may exert its anti-inflammatory effect through multiple mechanisms.
Dapsone is available as a 5% gel formulation, which contains 50 mg of dapsone (Aczone).
Aczone is marketed by Allergan, Inc. (2013; Irvine, CA, USA). The product was launched in 2008 and is currently available only in the United States and Canada.
Dapsone is a sulfone antibacterial agent.
USE IN ACNE
The use of oral dapsone in acne is limited by the potential for adverse effects, and recently, the drug has been resurrected as a topical preparation. It was introduced to the United States and Canadian market in 2008 and approved by the Food and Drug Administration for the management of acne vulgaris. The efficacy of Aczone has been evaluated in two randomized, double-blind placebo-controlled clinical studies that were combined in a single publication (Draelos et al., 2007). The results show that 12 weeks of treatment with Aczone reduced the number of inflamed lesions by nearly 50% (compared with baseline) and noninflamed lesions by 32%. Although these reductions were deemed statistically significant, the vehicle itself reduced inflamed and noninflamed lesion counts by 42% and 24%, respectively, highlighting that the improvement compared with vehicle was modest. Dapsone has been studied in combination with adapalene or benzoyl peroxide (Fleischer et al., 2010). The reduction in lesions was significant compared with placebo, but there was no discernible difference when dapsone was used in conjunction to either agent. More recently, the addition of dapsone to tazarotene 0.1% was compared with tazarotene alone (Tanghetti et al., 2011) in the management of acne. The results showed a reduction in total lesion count of 63% (compared with baseline) for the combination versus 53% for tazarotene alone.
These efficacy studies clearly show that topical dapsone is an effective treatment in acne, but until data from comparative studies become available, the circumstances that warrant prescription of topical dapsone remain to be determined.
Aczone should be applied twice daily for up to 12 weeks.
There are no contraindications to the use of Aczone. However, oral dapsone is known to cause hemolysis (the abnormal breakdown of red blood cells), which may result in hemolytic anemia. The potential for hemolysis is raised if the individual has glucose-6-phosphate dehydrogenase deficiency (G6PD). Known triggers for hemolysis in individuals with G6PD include infections and the use of drugs such as dapsone (Pamba et al., 2012). Consequently, there is the potential for hemolysis in patients with G6PD deficiency prescribed Aczone. In a 12-week study of the hematological safety of Aczone in acne patients with G6PD deficiency, there was evidence of mild hemolysis in some patients shown by a 0.32-g/dl drop in hemoglobin although, overall, there was no clinical or laboratory evidence for hemolytic anemia (Piette et al., 2008). As a precautionary measure, the manufacturer recommends that, if signs or symptoms of hemolytic anemia (such as sudden onset of back pain, breathlessness, tiredness/weakness with daily activities, dark-brown urine, high fever, and yellow or pale skin) develop while using Aczone, the gel should be discontinued. It is also recommended that Aczone is not used if patients are taking dapsone or other antimalarials because of the potential for hemolytic reactions (Allergan, Inc., 2013).
PREGNANCY AND LACTATION
Aczone has not been tested in pregnant women, and although oral dapsone has been known to be embryocidal in animal studies using very high doses, the manufacturer suggests using Aczone in pregnancy only if the benefits of treatment outweigh any potential risks. Oral dapsone is excreted in breast milk, and although systemic levels from topical application are very low, the manufacturer recommends that nursing mothers either discontinue nursing or stop the drug.
Use of double strength (160/800 mg) trimethoprim-sulfamethoxazole in combination with Aczone did lead to an increase in dapsone and its metabolite, N-acetyl-dapsone, although systemic levels were still 100-fold less than oral dapsone at therapeutic levels (Thiboutot, Willmer, Sharata, Halder, & Garrett, 2007). In the study by Fleischer et al. (2010), a potential drug interaction was noted by seven patients in the Aczone and benzoyl peroxide group. This interaction involved the development of a yellow-to-orange discoloration of the skin, which lasted between 4 and 57 days.
Many of the adverse effects are predictable, similar to other topical therapies, and limited to the site of application. Such effects include erythema, dryness, oiliness, and skin peeling. The incidence of such effects was reported as being moderate in no more than 6% of patients using Aczone. Using alternate days (or even less frequently) and gradually increasing the frequency of application to daily may minimize the severity of such side effects. Patients should be aware of possible local and rarely systemic side effects and discuss any concerns with the prescriber.
IMPLICATIONS FOR DERMATOLOGY NURSES
Acne is a condition that often appears in teenage years. Responses to acne range from mild annoyance to depression and even suicidal ideation (Penzer & Ersser, 2010). Aktan, Ozmen, and Sanli (2000) found acne results in higher levels of anxiety in adolescent girls. Use of a tool such as the Cardiff Acne Disability Index (Motley & Finlay, 1992) can help with assessment and discussion on the impact an individual’s acne has on his or her quality of life.
Education is fundamental to the successful management of acne, and it is essential that patients understand that the condition responds slowly to treatment because most topical therapies prevent formation of new lesions rather than target existing ones. Improvements may not be apparent until 4 weeks, and one primary care study in United Kingdom found that the greatest improvement in acne severity occurred within the first 6 weeks of treatment (Ozolins et al., 2004). Treatment should be continued for at least 12 weeks before a decision to alter therapy is made. There are currently no treatments for acne scarring that have a good research evidence base (Penzer & Ersser, 2010), so realistic advice regarding existing acne scars is important, coupled with encouragement to use active treatment to help prevent subsequent scarring. A nursing consultation is ideal for a discussion regarding the facts and myths about acne and a good opportunity to talk to individuals about their health and well-being identifying areas that they may wish to improve. Although studies in the past have refuted a link between diet (especially chocolate or junk food), more recent research provides some evidence that a low glycemic index diet (based on fruits, vegetables, and low intake of processed foods) improves acne severity (Smith, Mann, Braue, Makelainen, & Varigos, 2007, Won et al., 2012).
To use treatments effectively, however, depends on more than having a treatment and knowing what it does. Bandura (1997) identifies that people are more likely to engage in certain behaviors when they believe they are capable of carrying out those behaviors and that perceived self-efficacy is concerned not with the number of skills people have but with what they believe they can do with what they have. This highlights the need for nurses not only to educate regarding treatments but also support people through their treatment. Penzer and Ersser (2010) note the importance of the “concordance process” far beyond the traditional expectation of compliance. To be a partner in their own care, an individual requires knowledge about the treatment and how to use it as well as a belief in its efficacy.
Patients often incorrectly assume that acne is associated with poor hygiene and that increased washing, especially with abrasive agents, will help. It is unnecessary to wash the skin more than twice a day and preferable to use lukewarm water (not hot or cold) and a mild soap. Abrasive or exfoliating agents are not necessary and may even cause further inflammation. The skin should also be washed before application of Aczone.
The use of thick, heavy makeup, although often applied to mask spots, may worsen acne, and patients should choose oil-free or noncomedogenic make-up. Some women may find that their acne worsens in the week before menses. All patients should be made aware that picking and squeezing at spots can worsen acne as can occupations, which involve long periods of time in hot or humid environments such as kitchens. Many topical acne products can lead to skin dryness, and if this becomes a problem, a water-based emollient cream can be used. Heavy, oil-rich creams or ointments are best avoided because these can clog pores and potentially worsen acne. Patients should also understand that topical treatments should be applied to acne prone areas and not just on individual lesions.
Dapsone has been used in medicine for 70 years, and although previously advocated as a useful oral therapy for acne, side effects and the introduction of isotretinoin have largely replaced dapsone, which is still recommended and licensed for the treatment of dermatitis herpetiformis. However, the introduction of a topical preparation has revived interest in dapsone in the management of mild-to-moderate acne. The available data clearly show the topical dapsone is an effective agent, but the lack of head-to-head studies with established treatments means that its place in the management of mild-to-moderate acne remains to be determined.
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Acne Vulgaris; Efficacy; Pharmacology; Safety; Supporting Patients; Topical Dapsone
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