Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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Sandra A. Kopp and Justin J. Green
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Recurrent aphthous stomatitis (RAS) is the most common cause of oral ulceration. Aphthae, or ‘canker sores’, are characterized by the recurrence of one or more painful, shallow, sharply marginated ulcerations with a fibrinous base and surrounding erythematous halo on mobile, non-keratinized, oral mucosa. Three main types include minor, major, and herpetiform aphthae, which differ in size, duration, number, potential for scarring, and location of ulcerations. The etiology remains unclear; however, genetic predisposition, nutritional deficiencies, infections, hormonal changes, immunodeficiency, and environmental agents have been implicated. It is important to differentiate aphthae from other mucosal ulcerations, including herpes simples virus (HSV), other viral and bacterial infections (Epstein-Barr virus, cytomegalovirus, varicella zoster virus, coxsackie virus, syphilis, gonorrhea, tuberculosis), erythema multiforme, lichen planus, autoimmune bullous diseases (pemphigus vulgaris and cicatricial pemphigoid), contact dermatitis, chronic ulcerative stomatitis, and trauma before therapy is initiated. Malignancy and systemic vasculitis must also be considered in lesions that are not self-resolving.
The therapeutic approach to aphthae is dependent on the frequency of recurrence, duration, and severity of symptoms. In addition, underlying hematologic abnormalities, nutritional deficiencies, and medications should be considered as causative agents, as well as many systemic disorders such as inflammatory bowel disease, Crohn disease, Behçet disease, mouth and genital ulcers with inflamed cartilage syndrome (MAGIC syndrome), cyclic neutropenia, Sweet syndrome, reactive arthritis, HIV infection, and auto-inflammatory syndromes such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA syndrome). Stress is also thought to play a role in exacerbation of the disease. Unfortunately, because there is no curative treatment to date, the emphasis of treatment is on measures that may afford symptomatic relief and decrease occurrence, without significant adverse effects.
Topical corticosteroids are the mainstay of therapy. For milder disease, corticosteroids such as fluocinonide can be used. More potent corticosteroids such as clobetasol or halobetasol are appropriate for more severe episodes. Most practitioners suggest the use of topical therapy after meals. These can be applied in equal parts with an occlusive dressing such as Orabase for better adherence. Drug delivery can be enhanced by cotton-tip applications for 30 seconds and avoidance of eating and drinking for 30 minutes after application. Initial concentrations of 3–10 mg/mL of intralesional triamcinolone acetonide are helpful for major aphthae. Repeat injections over 2- to 4-week intervals are advised. Dexamethasone elixir 0.5 mg/5 mL three times daily used as a mouthwash or beclomethasone dipropionate aerosol spray can target ulcers on the soft palate or oropharynx. Elixirs can be combined with sucralfate or kaopectate to improve adhesion to ulceration. When used for less than 3 weeks, systemic absorption and hypothalamic-pituitary-adrenal axis suppression are unlikely.
RAS that elicits severe pain may require intermittent systemic corticosteroid therapy. Prednisone 1 mg/kg (40–60 mg) daily can be given with a 2-week taper or as ‘burst therapy’ for shorter periods. Concomitant therapy with topical corticosteroids may be helpful. Colchicine 0.6 mg two to three times daily and thalidomide 50–200 mg daily are the most effective steroid-sparing agents. Thalidomide is the only FDA-approved treatment for major aphthae in HIV-positive patients. Dapsone 100 mg daily, pentoxifylline 400 mg three times daily, and clofazimine 100 mg daily may also lead to suppression of aphthae. Anti-tumor necrosis factor (TNF-α) therapies may be effective in recalcitrant cases. Those patients who require suppressive therapy but cannot tolerate the side effects of systemic agents can try medications such as topical cyclosporine rinse 500 mg/5 mL three times daily, or interferon–α2a 1200 IU daily as a 1-minute rinse and swallow.
Application of amlexanox 5% paste four times daily has been shown to reduce aphthous ulcer healing time, and the application of amlexanox OraDisc four times daily to prodromal areas of the buccal mucosa has shown promise in the prevention of recurrent minor aphthous ulceration.
Topical anesthetics such as lidocaine gel or spray, dyclonine, diphenhydramine (12.5/5 mL) or benzocaine are helpful for pain reduction. Patients must avoid desensitization of the entire oral vault, which may lead to self-induced trauma. A compounded anesthetic mouthwash (aluminum hydroxide–magnesium hydroxide, diphenhydramine, and lidocaine) has better mucosal adherence. Systemic non-steroidal anti-inflammatory drugs (NSAIDs), sucralfate suspension, 0.2% chlorhexidine gluconate mouthwash, triclosan, or tetracycline suspension (250 mg/5 mL) may provide pain relief and reduce healing time, although these are less effective than potent topical corticosteroids. Bioadhesives such as carboxymethylcellulose provide a protective film and may reduce healing time.
Trigger avoidance can be useful. Predisposing factors include food (nuts, chocolate, tomatoes, citrus fruits, and spices), alcohol and carbonated beverages, trauma, menstruation, and stress. A food diary may be of value in identifying an offending agent. Certain medications, such as β-blockers, NSAIDs, and antioxidants, as well as sensitivity to sodium lauryl sulfate found in toothpaste, may contribute to the recurrence of aphthae. Hormonal therapy may alleviate RAS associated with menstruation. Reassurance of the benignity of this condition is paramount, and relaxation techniques or biofeedback can be discussed if stress is found to be a significant trigger.
Complete blood count
Vitamins B1, B2, B6, and B12, folate, zinc, and iron levels
Culture/polymerase chain reaction of aphthae to exclude herpes simplex virus
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Review article containing the summary of possible etiologies and clinical presentations of aphthae, differential diagnosis, and treatment options.
Scully C, Porter S. Br J Oral Maxillofac Surg 2008; 46: 198–206.
Review article highlighting possible etiologies and differential diagnosis of RAS. This article recommends checking complete blood count, folate, iron studies, and B12, as well as excluding infections or systemic diseases that may include aphthae-like ulcerations, namely Behçet disease and HSV.
Compilato D, Carroccio A, Calvino F, Di Fede G, Campisi G. J Eur Acad Dermatol Venerol 2010; 24: 667–73.
Thirty-two patients with RAS and 29 healthy controls were subjected to hematological investigations. Deficiencies were noted in 56.2% of RAS patients and 7% in controls. All patients with a negative family history of RAS showed complete remission after replacement therapy, while patients with a family history of RAS showed reduction in frequency and severity. The authors recommended that routine screening for serum iron, folic acid and vitamin B12 deficiencies should be performed
Baccaglini L, Lalla RV, Bruce AJ, et al. Oral Dis 2011; 17: 755–70.
Review article examining several myths about aphthous ulcerations, with specific emphasis of literature review of treatments in the last 6 years. They concluded that low-dose topical tetracyclines and amlexanox showed possible benefit. Outpatient procedures such as lasers or chemical cauterization provided rapid pain relief, but may not be feasible for frequent episodes.
Pimlott SJ, Walker DM. Br Dent J 1983; 154: 174–7.
In a single-blind clinical trial fluocinonide 0.05% ointment in Orabase applied up to five times daily was more effective than Orabase alone in reducing the duration of ulcers and increasing the number of ulcer-free days.
In some countries, triamcinolone in Orabase is more readily available.
Quijano D, Rodriguez M. Acta Otorrinolaringol Esp 2008; 59: 298–307.
This is a systematic review of published literature evaluating the effectiveness of topical corticosteroids in treating RAS. The authors were able to show a trend toward reduced healing times and decreased pain but commented on the lack of high-quality experiments in the literature.
Lui C, Zhou Z, Lui G, Wang Q, Chen J, Wang L, et al. Am J Med 2012; 125: 292–301.
This study is a randomized, double-blind, placebo-controlled, parallel, multicenter clinical trial which showed that dexamethasone 0.1% ointment three times a day for 5 days safely reduced the size and duration of aphthae compared to placebo.
Friedman M, Brenski A, Taylor L. Laryngoscope 1994; 104: 566–70.
Intralesional triamcinolone acetonide (40 mg/mL) was used in patients with AIDS having major aphthae that were present for at least 2 weeks and were culture negative for bacteria, viruses, fungi or acid-fast bacilli. Injections were administered every 2 weeks. Pain relief was achieved within 2 days in 94% of patients. One-half of affected patients had complete resolution after one injection.
Bell J. Clin Drug Investig 2005; 25: 555–6.
A review of four double-blind randomized control trials indicating that amlexanox 5% paste up to four times per day significantly reduced ulcer size compared to placebo.
Liu J, Zeng X, Chen Q, Cai Y, Chen F, Wang Y, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 475–81.
Patients (n = 212) with oral aphthae were enrolled in a randomized, double-blind, vehicle-controlled, clinical trial. Amlexanox 5% adhesive tablets or placebo was applied four times daily to the ulcer. Patients were evaluated at day 4 and day 6. The reduction in ulcer pain and lesion size was statistically significant at day 4, and reduction of all parameters, including erythema and exudation, was statistically significant at day 6. No systemic side effects were reported.
Graykowski EA, Kingman A. J Oral Pathol 1978; 7: 376–82.
A suspension of tetracycline 250 mg/5 mL was used four times daily in patients with RAS. The suspension was held in the mouth for 2 minutes and then swallowed. This study found that tetracycline therapy significantly reduced ulcer duration, size and pain, but did not alter the recurrence rate.
Other studies using tetracycline or its derivatives (topically or orally) have drawn similar conclusions.
Hunter L, Addy M. Br Dent J 1987; 162: 106–10.
This crossover study included 38 patients who used 0.2% chlorhexidine gluconate mouthwash three times daily for 6 weeks. The total number of days with ulcers was significantly reduced, and the interval between successive ulcers was increased.
Gel and mouthwash formulations of 0.1% chlorhexidine have also been efficacious. Chlorhexidine mouthwash is not associated with systemic side effects, but can stain teeth.
Meiller TF, Kutcher MJ, Overholser CD, Niehaus C, DePaola LG, Siegel MA. Oral Surg Oral Med Oral Pathol 1991; 72: 425–9.
A 6-month double-blind study compared Listerine™ antiseptic and a hydroalcoholic control used as a vigorous mouthwash twice daily. The duration of ulcers and pain severity were significantly reduced in the Listerine group. Both the Listerine group and the control group experienced a reduced incidence of ulcers.
Skaare AB, Herlofson BB, Barkvoll P. J Clin Periodontol 1996; 23: 778–81.
In a double-blind crossover study, 0.15% triclosan mouthwash caused a significant reduction in the number of ulcers during the experimental period. Compared to the 7.8% ethanol and triclosan formulation, the efficacy of the mouthwashes was reduced when propylene glycol or a higher concentration of ethanol (15.6%) were used as solubilizing agents.
Rattan J, Schneider M, Arber N, Gorsky M, Dayan D. J Intern Med 1994; 236: 341–3.
Sucralfate applied four times daily to ulcers was found to be superior to antacid (aluminum hydroxide and magnesium hydroxide) and placebo with regard to duration of pain, reduction in healing time, response to first treatment, and duration of remission. The 2-year prospective, randomized, double-blind, placebo-controlled, crossover trial included 21 patients unresponsive to conventional therapy.
A randomized, placebo-controlled, double-blind study of sucralfate applied four times daily to oral and genital ulcerations of Behçet disease resulted in reduced frequency, healing time and pain in oral ulcerations, and reduced healing time and pain in genital ulcerations.
Rodu B, Russell CM. Oral Surg Oral Med Oral Pathol 1988; 65: 699–703.
Zilactin, which contains hydroxypropyl cellulose, led to pain relief after an acidic challenge followed by rechallenge.
Orabase, which contains carboxymethylcellulose, has been beneficial in trials when combined with topical corticosteroids, possibly owing to its adhesive properties.
Mimura MA, Hirota SK, Sugaya NN, Sanches JA Jr, Migliari DA. Clinics 2009; 64: 193–8.
An open, 4-year clinical trial of 21 patients with RAS treated with thalidomide (100 mg/day), dapsone (100 mg/day), colchicine (1.5 mg/day), and pentoxifylline (400 mg three times a day). Thalidomide was the most efficient and well tolerated. Dapsone and colchicine provided good results; however, dapsone was not well tolerated. Pentoxifylline was mildly effective.
Pakfetrat A, Mansourian A, Momen-Heravi F, Delavarian Z, Momen-Beitollahi J, Khalilzadeh O, et al. Clin Invest Med 2010; 33: E189–95.
In this double-blind randomized clinical trial, 34 patients with RAS were split into two groups: prednisolone 5 mg daily, or colchicine 0.5 mg daily, for 3 months. Both medications were equally effective in reducing pain, re-occurrence, size, and number of aphthae, although colchicine had a higher rate of side effects.
Lynde CB, Bruce AJ, Rogers RS. Arch Dermatol 2009; 145: 273–6.
A retrospective review showing clinical improvement in RAS with colchicine (1.2 mg/day), dapsone (150 mg/day), and the combination of the two.
Vincent SD, Lilly GE. Oral Surg Oral Med Oral Pathol 1992; 74: 79–86.
‘Burst therapy’ with prednisone 40 mg once daily for 5 days, followed by 20 mg every other day for 1 week in addition to topical triamcinolone acetonide 0.1% or 0.2% four times daily, led to complete or partial control of aphthae in 12 of 13 patients.
Katz J, Langevitz P, Shemer J, Barak S, Livneh A. J Am Acad Dermatol 1994; 31: 459–61.
Twenty patients with RAS were studied in a 4-month open, prospective trial. During therapy with colchicine 0.5 mg three times per day, the mean aphthae count and the mean pain score decreased by 71% and 77%, respectively.
Revuz J, Guillaume JC, Janier M, Hans P, Marchand C, Souteyrand P, et al. Arch Dermatol 1990; 126: 923–7.
A multicenter crossover randomized, double-blind trial of thalidomide 100 mg daily versus placebo led to complete remission in 32 of 67 (48%) patients treated with thalidomide and in six of 67 (9%) patients treated with placebo. Side effects, which included drowsiness, constipation, headache, vertigo, and neuropathy, resulted in treatment interruptions in 11 patients.
Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med 1997; 336: 1487–93.
Fifty-seven HIV-positive patients were included in this double-blind, randomized, placebo-controlled study of thalidomide 200 mg daily versus placebo as therapy for oral aphthous ulcers in HIV-infected patients. Sixteen of 29 patients in the thalidomide group (55%) had complete healing of their aphthous ulcers after 4 weeks, compared to only two of 28 patients in the placebo group (7%).
Cheng S, Murphy R. Clin Exp Dermatol 2012; 37: 132–5.
Retrospective review of 15 patients treated with thalidomide after failing topical and oral steroids. Out of 15 patients, 14 showed improvement with thalidomide; however, nine patients showed a decline in their nerve conduction study, independent of dose. Despite these findings only three patients stopped the medication, and the patient with the largest decline in nerve conduction (80%) opted to continue thalidomide rather than risk re-occurrence of the ulcerations.
Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Medicine 2010; 89: 176–82.
This multicenter retrospective cohort study of 92 patients with severe RAS demonstrated 85% complete remission from thalidomide within a mean of 14 days. Mild adverse events were noted in 78% of patients. Twenty-one percent had severe events, including thromboembolism and peripheral neuropathy.
Sharquie KE, Najim RA, Al-Hayani RK, Al-Nuaimy AA, Maroof DM. Saudi Med J 2008; 29: 734–8.
In this double-blind placebo controlled study of 45 patients with RAS, patients were treated with zinc sulfate 150 mg twice daily, dapsone 50 mg twice daily, and glucose 250 mg daily as placebo. Results showed that both zinc sulfate and dapsone had significant therapeutic effects in decreasing ulcer size. They concluded that zinc sulfate had much more rapid and sustained action.
Thornhill MH, Baccaglini L, Theaker E, Pemberton MN. Arch Dermatol 2007; 143: 463–70.
Twenty-six patients were randomized to pentoxifylline 400 mg three times daily or placebo. Patients taking pentoxifylline had less pain, smaller ulcers, fewer ulcers, and more ulcer-free days, but this was not statistically significant. However, smaller median ulcer size in the treatment group was statistically significant. Adverse events were common and included dizziness, headaches, gastrointestinal symptoms, and fatigue.
According to the study, patients taking the active drug stated that if it was shown to be effective in the treatment of aphthous ulcers, they would not want to use it because of the side effects.
Pizarro A, Navarro A, Fonseca E, Vidaurrazaga C, Herranz P, et al. Br J Dermatol 1995; 133: 659–60.
In patients with minor RAS receiving pentoxifylline 400 mg three times daily over a 6-month period, 50% did not experience a recurrence and 27% experienced a reduced number and duration of ulcers.
In other studies, over 50% of patients noted either complete resolution or a reduction in number and/or duration of ulcers during the treatment period. However, these are open-label trials involving small numbers of patients.
Eisen D, Ellis CN. J Am Acad Dermatol 1990; 23: 1259–64.
Four of eight patients with severe aphthous stomatitis obtained nearly complete suppression of ulcers during an 8-week course of topical cyclosporine 500 mg/5 mL, swish and rinse three times daily.
Hutchinson VA, Angenend JL, Mok WL, Cummins JM, Richards AB. Mol Biother 1990; 2: 160–4.
Oral administration of interferon-α2 (1200 IU daily) resulted in remissions of aphthae within 2 weeks of initiating therapy compared to no improvement in the placebo group. The placebo group was then treated similarly with interferon-α2 leading to complete remission of their aphthae.
Murphy GM, Griffiths AD. Clin Exp Dermatol 1989; 14: 330–1.
A 34-year-old woman was treated with etretinate 25 mg daily for plantar pustular psoriasis. Two-month remissions of her minor aphthae occurred with two courses of etretinate.
Colvard M, Kuo P. J Am Dent Assoc 1991; 122: 51–3.
Pain alleviation was observed in 16 of 18 patients following CO2 laser therapy of minor aphthae.
Zhou Y, Chen Q, Meng W, Jiang L, Wang Z, Liu J, et al. Oral Surg Oral Med Oral Radiol Endod 2010; 109: 561–6.
A randomized double-blinded control trial in 258 non-penicillin allergic Chinese patients was performed with subjects split between placebo, treatment, and no-treatment groups. Patients treated with penicillin G potassium troches showed significant objective decreased ulcer size and subjective decrease in pain.
Robinson ND, Guitart J. Arch Dermatol 2003; 139: 1259–62.
A case report of treatment of recalcitrant RAS with subcutaneous etanercept 25 mg twice weekly with a resultant decrease in frequency, severity and duration of flares during the 7 months of therapy.
Sanchez-Cano D, Callejas-Rubio JL, Ruiz-Villaverde R, Ortega-Centeno N. J Eur Acad Dermatol Venereol 2009; 23: 206.
This is the second reported case of adalimumab 40 mg subcutaneously every other week resulting in dramatic improvement in RAS.
Guenova E, Hoetzenecker W. Arch Dermatol 2001; 147: 282–4.
In this case report, one patient was treated with 30 mg dimethylfumarate and 67 mg monoethylfumarate daily and increased weekly to a maximum dose of 240 mg dimethylfumarate and 174 mg monoethylfumarate daily, which was well tolerated. All lesions resolved in 8 days with no re-occurrences during her 6 months of therapy. She remained clear until 11 months after stopping therapy.
de Abrue MA, Hirata CH, Pimentel DR, Weckx LL. Oral Surg Oral Med Oral Pathol Radiol Endod 2009; 108: 714–21.
In this randomized controlled partially blinded study, clofazamine (100 mg daily × 30 days, then 100 mg every other day) and colchicine (0.5 mg three times a day) were investigated for 6 months in the treatment of RAS. Patients taking clofazimine showed significant improvement to colchicine at the second, third, fifth, and sixth months of therapy.
Yasui K, Kurata T, Yashiro M, Tsuge M, Ohtsuki S, Morishima T. Acta Paediatr 2010; 99: 442–5.
In this study, 16 patients with minor RAS were given daily vitamin C (2000 mg/m2) for 3 months. Treatment was then discontinued for 3 months, and then restarted for another 3 months. Patients experienced a significant decrease in stomatitis during treatment months as compared to months without treatment.
Volkov I, Rudoy I, Freud T, Sardal G, Naimer S, Peleg R, et al. J Am Board Fam Med 2009; 22: 9–16.
This randomized, double-blind, placebo-controlled trial of 58 patients with RAS were split into treatment with 1000 µg of sublingual vitamin B12 and placebo. No patients had baseline B12 levels less than 150 pg/mL. The treatment group has significantly fewer outbreaks than the controls, regardless of baseline B12 level.
Of note, there have also been several studies negating the benefits of vitamin replacement in the literature.
Alidaee MR, Taheri A, Mansoori P, Ghodsi SZ. Br J Dermatol 2005; 153: 521–5.
Ninety-seven patients with painful minor aphthae were randomized to receive one stick application of silver nitrate cautery or placebo. After 1 day, a statistically significant reduction in severity of pain was shown. Silver nitrate did not prolong or shorten healing time examined after 7 days. No side effects were noted.
The authors note that the treatment is simple and cost-effective for patients, with few recurrences.
Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 402–7.
In this double-blind, randomized placebo-controlled trial of 60 patients with minor RAS patients were split equally into treatment groups of prednisone 25 mg daily tapered over 2 months, 10 mg montelukast daily for 1 month, then every other day for the second month, and cellulose (placebo). Both interventions significantly reduced number of lesions and pain relief compared to placebo; however, prednisone was more effective than montelukast. This suggests montelukast may be a safer alternative to prednisone.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Vitamin and mineral deficiency replacement
Topical corticosteroids
Amlexanox 5% paste
Intralesional corticosteroids
Tetracycline suspension
Antimicrobial mouth rinses
Sucralfate
Hydroxypropyl cellulose/carboxymethylcellulose
Oral corticosteroids
Colchicine
Thalidomide
Dapsone
Zinc sulfate
Pentoxifylline
Clofazimine
Ascorbate
Vitamin B12
Topical cyclosporine
Oral interferon-α2a
Etretinate
CO2 laser
Penicillin G potassium troches
Etanercept
Adalimumab
Silver nitrate
Fumaric esters
Montelukast
