continuing medical education Selecting Topical and Systemic Agents for Recurrent Aphthous Stomatitis Drore Eisen, MD, DDS, Cincinnati, Ohio Denis P. Lynch, DDS, PhD, Memphis, Tennessee GOAL To discuss topical and systemic medications used for palliation of recurrent aphthous stomatitis (RAS). OBJECTIVES Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Contrast the characteristics of recurrent aphthous stomatitis and intraoral herpes simplex virus infection. 2. Discuss topical treatments and their efficacy for RAS. 3. Summarize systemic treatments for RAS. CME Test on page 214. This article has been peer reviewed and ACCME to provide continuing medical ed- approved by Michael Fisher, MD, Professor ucation for physicians. of Medicine, Albert Einstein College of Albert Einstein College of Medicine Medicine. Review date: August 2001. designates this educational activity for a This activity has been planned and im- maximum of 1.0 hour in category 1 credit plemented in accordance with the Essen- toward the AMA Physician’s Recognition tials and Standards of the Accreditation Award. Each physician should claim only Council for Continuing Medical Education those hours of credit that he/she actually through the joint sponsorship of Albert spent in the educational activity. Einstein College of Medicine and Quadrant This activity has been planned and HealthCom, Inc. The Albert Einstein produced in accordance with ACCME College of Medicine is accredited by the Essentials. Recurrent aphthous stomatitis (RAS) is one of the scribed corticosteroids, or antimicrobial agents, most common oral diseases worldwide. Although are sufficient to control the disease. Patients with the exact etiology of RAS remains unknown, a frequent exacerbations or those with a severe variety of topical and systemic preparations may form of RAS that is unresponsive to topical treat- be used for palliation or prevention. In most ments often require systemic agents to control patients with RAS, topical agents, including over- their disease. These include corticosteroids, the-counter preparations such as amlexanox, pre- colchicine, dapsone, pentoxifylline, and thalido- mide. All therapies are palliative, and none result Dr. Eisen is in private practice in Cincinnati, Ohio. Dr. Lynch is a in permanent remission. Professor in the Department of Biologic and Diagnostic Sciences and in the Division of Dermatology, University of Tennessee ecurrent aphthous stomatitis (RAS), or Colleges of Dentistry and Medicine, Memphis. Reprints: Drore Eisen, MD, DDS, Dermatology Research canker sore, is the most common form of oral 1 Associates, 7691 Five Mile Rd, Cincinnati, OH 45230 Rulcerations in both children and adults. The (e-mail: [email protected]). clinical characteristics of RAS and differentiation VOLUME 68, SEPTEMBER 2001 201 RECURRENT APHTHOUS STOMATITIS Table 1. Clinical Characteristics of Recurrent Aphthous Stomatitis and Intraoral Herpes Simplex Virus Infection* Minor Major Herpetiform HSV RAS RAS RAS Infection Incidence Common Uncommon Rare Uncommon Location Buccal mucosa Labial mucosa All oral mucosa Hard palate Labial mucosa Soft palate Attached gingiva Lateral tongue Oropharynx Floor of mouth Number 1–10 1–5 5–100 1–10 Size, cm <1.0 >1.0 <0.3 0.1–1.0 Pain None to moderate Severe Mild to moderate None to moderate Duration, d 7–14 15–60 7–14 7–14 Scarring Rare Common None None Comments Multiple contributing History of HIV and No viral etiology History of HSV etiologic factors GI disease *RAS indicates recurrent aphthous stomatitis; HSV, herpes simplex virus; HIV, human immunodeficiency virus; GI, gastrointestinal. from ulcerations caused by intraoral herpes simplex systemic therapeutic modalities, which may pro- virus infection are outlined in Table 1. RAS is a vide symptomatic relief, are available (Table 2). multifactorial process, with the development of oral lesions influenced by trauma, smoking, stress, hor- Topical Treatments monal state, family history, food hypersensitivity, Amlexanox is a topical preparation that is effective and infectious or immunologic factors.2 Fortunately, in the treatment of RAS. The drug was approved by most cases of RAS can be managed palliatively with the US Food and Drug Administration in 1996 as the topical agents. A variety of over-the-counter prepa- first treatment for aphthous ulcers in immunocompe- rations containing one or more active ingredients, tent patients. Amlexanox is an anti-inflammatory including anesthetics, antimicrobials, wound that inhibits leukotrienes and histamines, although cleansers, coating agents, and occlusive dressings, is its exact mechanism of action in the treatment of widely available. Although many of these products RAS is unknown.3 In several double-blind, con- reduce the pain and/or shorten the duration of the trolled, multicenter studies involving more than disease, benefits are modest and attained typically in 1100 patients, amlexanox was shown to statistically patients with RAS whose ulcers are shallow, rela- accelerate complete ulcer healing and reduce the tively painless, and short in duration. time of pain resolution.4 Specifically, application of A significant number of patients with RAS amlexanox as a 5% paste to ulcerations resulted in develop painful ulcerations that result in difficulty complete resolution of pain 1.3 days sooner than no when speaking, eating, drinking, and performing treatment and 0.7 days sooner than vehicle alone. routine oral hygiene (Figure, A and B). Over- Similarly, amlexanox reduced complete healing by the-counter preparations are relatively ineffective 1.6 days compared with no treatment and by 0.7 days for these patients; however, multiple topical and compared with vehicle alone. 202 CUTIS® RECURRENT APHTHOUS STOMATITIS A B Minor aphthous ulcers (A) are small (less than 1 cm in diameter) shallow ulcers covered by a pseudomembrane and surrounded by erythema. Major aphthous ulcers (B) are larger, deeper, and heal with scar formation. Like corticosteroids, amlexanox should be multiple ulcerations. Corticosteroids are commonly applied 4 times daily (after meals and at bedtime). compounded with the occlusive dressing Orabase® Topical preparation, applied at the first sign of (Colgate-Palmolive, New York, NY), despite findings ulceration, significantly reduces pain and acceler- of a controlled study that suggests that topical ates healing. Patients may complain of burning or steroids in adhesive bases are no more effective than stinging at the site of application, but this adverse the base preparation alone.8 Patients should be reaction is transient. The vehicle, an oral paste instructed to apply topical corticosteroids 3 to 5 times specifically formulated to adhere to the oral daily and to initiate therapy during the early stage of mucosa, is well accepted by patients and often pre- lesion development. Prolonged contact of the corti- ferred to other topical agents. costeroid with the ulcerated mucosa appears to sig- Although rigorous controlled studies are lacking, nificantly increase the effectiveness of treatment. the efficacy of topical corticosteroids in the treat- Therefore, patients should massage the medication ment of RAS is indisputable based on their favorable on the ulceration for 30 to 60 seconds with their and widespread use. Furthermore, the lack of fingers or coat a cotton-tipped applicator and hold it observed or reported adverse effects of topical corti- against the ulceration for up to a minute. Eating and costeroids in the treatment of RAS and other oral drinking should be avoided for a minimum of inflammatory diseases supports their safety.5,6 30 minutes after application. Chronic topical corti- Several generalizations about topical cortico- costeroid use in the oral cavity can facilitate over- steroid use in the oral cavity may be made. Patients growth of Candida and requires careful monitoring. should be warned about the off-label use of these Although their benefits have not been substanti- agents and the accompanying package inserts, ated in multicenter trials, many antimicrobial com- which all state “for external use only.” As demon- pounds may be used to treat RAS with various strated in an open label study, superpotent topical degrees of success. For example, topically applied corticosteroids are more effective and rapid in onset antibiotics such as tetracycline and cephalexin may than weaker preparations.7,8 Because efficacy studies be helpful because of their anti-inflammatory effects.9 comparing corticosteroids in various vehicles have A solution containing a 250 or 500 mg antibiotic been performed only on the skin, choosing a vehicle capsule dissolved in 30 to 50 mL of water may be used for oral-cavity use is an inexact process that should as a rinse or to saturate gauze, which can be applied include patient preference. Ointments, unlike gels directly to the ulcer. Other antimicrobial compounds or creams, do not burn or sting when applied to including the mouthwash Listerine® (Warner- ulcerations, although they adhere poorly to mucosa. Lambert Consumer Healthcare, Morris Plains, NJ), Elixir forms of corticosteroids such as dexamethasone whose active ingredients include a mixture of essen- can be used as an oral rinse for patients with tial oils, can be used to decrease the duration and VOLUME 68, SEPTEMBER 2001 203 RECURRENT APHTHOUS STOMATITIS Table 2. Topical and Systemic Agents for Recurrent Aphthous Stomatitis* Agent Comment Topical Amlexanox Only FDA-approved drug for RAS Antibiotics