Oral hygiene: It is important to ensure appropriate oral hygiene and to avoid injury, since this leads to mouth ulcers.31,54 We recommend using a soft toothbrush, toothpaste that does not contain sodium lauryl sulfate (grade of recommendation [GR], A; level of evidence [LE], 1B),55,56 and an alcohol-free mouthwash.31,55,57

Eating: No relevant studies have appropriately addressed the role of diet in the management of RAS. In general, we should try to avoid products that are frequently associated with triggering flare-ups, especially if the patient reports an association with the products.54,57

Supplements: It is necessary to rule out nutritional deficiencies (e.g., vitamin B12, folic acid, iron, zinc) in patients with RAS, since in these cases, patients improve when they receive appropriate treatment (GR, C; LE, 4). Furthermore, one study showed that sublingual vitamin B12 at 1000  μg/d for 6 months could reduce the number of flare-ups and relieve pain in all patients with RAS independently of previous levels (GR, B; LE, 2B).56–58 Other studies have shown an improvement with ω-3 at 1000  mg/d for 6 months (GR, B; LE, 2B).59 In contrast, supplements with other vitamin complexes in patients without nutritional deficiency have not led to an improvement in symptoms or a reduction in the number of lesions (GR, B; LE, 2B).52,57,59,60

Topical anesthetics and barrier agents: These agents provide pain relief. They should be applied several times per day, preferably half an hour before meals and before teeth cleaning in order to facilitate their action and at bedtime. They can be used in combination with other treatments such as topical corticosteroids or amlexanox. The main protective and anesthetic agents include the following:

• •

  Lidocaine cream 1%, gel 2%, and spray: these are applied directly on the surface of the ulcers or in the form of mouthwashes (GR, B; LE, 2A).60

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  Benzocaine gel 20%: local anesthetic that relieves pain and reduces inflammation (GR, B; LE, 2A).61

• •

  Sucralfate suspension: a complex of aluminum hydroxide and sucrose sulfate complex that forms a protective barrier against ulcers. Several studies recommend mouth washing with 5 mL for 1-2  minutes 4 times daily (after teeth cleaning and at bedtime). This substance relieves pain, speeds up healing, and lengthens the interval between flare-ups (GR, B; LE, 2A).62,63

Topical antiinflammatory and antiseptic agents: These help to prevent superinfection by bacteria and fungi and improve oral hygiene.

• •

  Triclosan 0.15% in ethanol and zinc sulfate: Administered as 3 mouthwashes per day, this agent reduces the number of ulcers and the intensity of pain and increases the ulcer-free interval (GR, A; LE, 1B).63

• •

  Chlorhexidine 0.12%-0.2% in oral solution: 5 mL in rinses for 1-2 minutes 4 times daily (after teeth cleaning and at bedtime).60 Some studies report it to be less efficacious than sucralfate suspension (GR, B; LE, 2B).62

• •

  Diclofenac 3% in hyaluronic acid gel 2.5%: This agent proved superior to lidocaine in gel for reducing pain after 2-6 hours (GR, B; LE, 2A).60,63

Topical corticosteroids: These are the first-line agents for RAS60 and can be combined with topical anesthetics, antiseptics, and barrier agents. They provide pain relief and reduce the duration and frequency of flare-ups, although they take several days to exert an effect. They are more effective if used from the onset of the episode and are applied several times per day, preferably after teeth cleaning and at bedtime. The patient should be advised not to eat at least during the following half hour.62,64 The available options are as follows:

• •

  Triamcinolone acetonide 0.1% in Orabase: This is applied on the lesions 3-4 times per day. It has proven to be a safe and effective treatment (GR, B; LE, 2B).60

• •

  Dexamethasone solution (0.5 mg/5 cc) or ointment: Rinsing every 5 minutes, 3-4 times per day or applying the ointment on the ulcers 3 times per day has proven to be effective and safe (GR, A; LE, 1B).59,64

• •

  Clobetasol 0.05% in gel, ointment, or Orabase: The agent is applied to the lesions 2-3 times per day. As this is the most potent corticosteroid, it is reserved for the most severe cases.60

Amlexanox 5%: Topical inflammatory agent that, when applied on the lesions in the form of a 5% paste 4 times per day (after meals and at bedtime) has proven to be effective for the management of pain and for speeding up healing in several studies (GR, B; LE, 2B).52,56,61,65 Amlexanox 5% is one of the most cost-effective topical treatments, together with triamcinolone acetonide.61

Cauterization: Applied with hydrogen peroxide 0.5% solution or silver nitrate 1%-2%, this approach reduces pain and speeds up healing (GR, B; LE, 2B).56,57

Other topical treatments: Many other topical treatments have been used, including tetracyclines in mouthwash, doxycycline in denture adhesive, nicotine gum, liquid diphenhydramine mouthwash, or camel thorn distillate, most of which have been reported in poor-quality studies, with disparate results and no evidence to recommend their use.52,57,66,67

Patients who experience severe and/or frequent episodes of RAS that are refractory to general care and to topical treatments (see above) should consider adding a systemic treatment. This is selected based on the severity of symptoms, comorbid conditions, and the patient’s tolerance and preferences.

Oral corticosteroids: Oral corticosteroids have been used effectively in long regimens at lower doses, for example, oral prednisone at 5  mg/d for 3 months (GR, B; LE, 2A),67 and in shorter regimens, with doses of 20 to 40  mg/d for 4-7 days, with subsequent gradual reduction of the dose. This leads to relief of pain, faster healing, and a reduction in the number of episodes (GR, B; LE, 2A).52,54,56,57

Alternative systemic agents should be considered in patients who do not respond to intermittent therapy with systemic corticosteroids, patients who require frequent or longer courses of corticosteroids, and patients who cannot undergo treatment with corticosteroids for other reasons.

Colchicine: Colchicine is an antimitotic drug with specific immunomodulatory and antifibrotic effects. It has been used at 0.5 to 2 mg/d, with various results.52,56,57 In some publications, it is considered a systemic drug of choice at doses of 1-2 mg/d over long periods, depending on the severity of symptoms and tolerance.56,57,68 In contrast, after an analysis of published studies, the 2012 Cochrane review52 concluded that this drug was not useful in comparison with oral corticosteroids for the treatment of RAS, since its efficacy rates are equal to or lower than those of corticosteroids, although it has a greater rate of adverse effects (mainly affecting the gastrointestinal tract) (GR, B; LE, 2A).52,69,70

Thalidomide: Thalidomide has been used at 50 to 100 mg/d for several months with good results.56,57,70 A study performed in Brazil showed it to be more effective and better tolerated than dapsone, colchicine, and pentoxyphillin.71 We must remember that this drug is teratogenic and can cause sleepiness, paresthesia, and irreversible peripheral neuropathy. Therefore, patients should be carefully selected and informed. It is also advisable to take a history and perform an examination at all follow-up visits to rule out signs of peripheral neuropathy. If this condition is suspected, treatment should be discontinued and an electromyogram ordered (GR, B; LE, 2B).56,57,70

Dapsone: Dapsone reduces the number and size of the ulcers.63 It is usually started at 25-50 mg/d, increasing to a maximum of 150 mg/d depending on the response and on tolerance. Glucose-6-phosphate dehydrogenase should be determined before starting therapy with dapsone (GR, B; LE, 2A).60,67

Montelukast: Montelukast is a leukotriene inhibitor that, in some trials, has been shown to improve pain and accelerate healing of mouth ulcers, as well as reduce the appearance of new lesions with a dose of 10  mg/d for 1 month, followed by 10 mg every 2 days for a further month.72 Montelukast is less efficacious than prednisone, although it has fewer adverse effects and is very well tolerated. Therefore, it could prove to be a good option for long-term treatment (GR, B; LE, 2B).52,56,72

Clofazimine: Clofazimine is an antimicrobial agent that has been used at 100 mg/d for 30 days followed by 100 mg every other day for 6 months. In a study with a high risk of bias, it improved symptoms and reduced the number of flare-ups compared with colchicine (GR, B; LE, 2B).52,69

ß-Glucans: ß-Glucans comprise a group of polysaccharides found in some bacteria, plants, and fungi. They have been used at doses of 10 mg of 1,3-1,6 ß-glucan twice daily, with an improvement in the severity of the ulcer compared with placebo.52,73 Evidence in favor of or against this approach in RAS is insufficient (GR, B; LE, 2B).52

Pentoxifylline: This nonselective phosphodiesterase inhibitor with hemorheological properties specifically inhibits production of TNF-alfa and possibly production of some other type 1 helper T cells and proinflammatory cytokines such as IL-1ß, which are thought to play an important role in the development of RAS. Pentoxifylline has been used at 400 mg/8 h, with improvement of the lesions, although these recur when the drug is discontinued. Evidence in favor or against its use is insufficient (GR, B; LE, 2A).52,63

Levamisole: Levamisole is an anthelmintic and immunomodulatory agent.60 Results from trials with doses of 50 mg/8 h for 3 to 11 days per flare-up for at least 6 months show disparate efficacy outcomes, with insufficient evidence in favor of or against its use (GR, B; LE, 2A).52,62

Doxycycline: Doxycycline at 20 mg/12 h revealed no differences with respect to placebo in a study with a high risk of bias (GR, B; LE, 2A).52

Anti-TNF-alfa: Data from case series show that anti-TNF alfa agents (etanercept, adalimumab, infliximab, and golimumab) have been used successfully for treatment of severe and recalcitrant RAS.62,74 This seems to be a specific class effect, with no significant differences between the anti-TNF agents used. Furthermore, it seems that failure with any of these drugs does not imply the lack of a response to other anti-TNF agents (GR, C; LE, 4).62,74 These drugs should be chosen based on disease severity, efficacy, potential adverse effects, and costs.

CO2, Nd:YAG, and diode laser: Some studies showed that laser therapy had similar or superior efficacy to topical corticosteroids,67 with immediate relief of pain and accelerated healing of the ulcers (GR, B; LE, 2A).53,57,75

Apremilast: Apremilast is an oral phosphodiesterase-4 inhibitor. In one published case of major RAS that was refractory to multiple topical and systemic treatments, 6 weeks’ treatment with apremilast (loading dose of 10 mg/d increasing progressively to 30 mg/12 h) led to complete resolution of the lesions, with no recurrences after 1  year of treatment (GR, C; LE, 4).76

Bee propolis: This resinous material is produced by bees and is obtained from the buds of poplars and conifers. One study with a high risk of bias showed that a daily capsule of 500 mg taken over 6 months led to a reduction in the number of outbreaks. However, evidence was insufficient to recommend or not recommend its use (GR, B; LE, 2A).52,77

Homeopathy: One study with a high risk of bias concluded that homeopathy could improve pain and accelerate the cure of ulcers, without there being sufficient evidence for recommending or not recommending its use (GR, B; LE, 2A).52,78

Traditional Chinese medicine: Some traditional therapies have been used for hundreds of years. A recent review tried to evaluate the scientific aspects of this approach by evaluating several of the treatments used, such as Liuwei Dihuang pills (composed of Cornus officinalis, Rehmannia glutinosa, Rhizoma dioscoreae, Cortex moutan radicis, Poria cocos, and Alisma plantago-aquatica), bergamot, Qing Wei powder, and Yiqing capsules. The authors concluded that some treatments in traditional Chinese medicine may be effective and safe for the treatment of RAS, although high-quality studies would be necessary to confirm these findings. Evidence to recommend their use is insufficient (GR, B; LE, 2B).79

Several publications address the drugs used in the treatment of oral aphthous ulcers that manifest in systemic diseases, such as Behçet disease, but not in RAS per se. These include azathioprine, methotrexate, ciclosporin, and interferon-alfa. Given that neither their efficacy with respect to the etiology and pathogenesis of aphthous ulcers nor their role in RAS has been studied, we decided not to include these drugs in order to avoid confusion.80–83