a)     Topical gels, creams, ointments and pastes

These topical agents are considered first line treatment of RAUs. They are cheap, effective and safe.

There are issues with sufficient contact time of the drug system to ensure adequate absorption of the drug before it is rubbed or rinsed away. This is addressed by using different kinds of adhesive vehicles in combination with the drug (e.g. Orabase, Bristol-Myers Squibb; isobutyl-cyanoacrylate or Iso-Dent, Ellman International) (4).

Pastes and gels (3) coat the surface of the ulcers and form a protective barrier against secondary infection and further mechanical irritation. (5)

The ulcerated area should be dry and only a small amount of gel or cream should be applied after rinsing. Eating or drinking should be avoided for 30 minutes after application. Application should be repeated three or four times daily while an ulcer is present.

b)      Anti-microbial Mouthwashes (1,5,7)

Research suggests that antibacterial mouth rinses can enhance the healing time of aphthous ulcers and also help to minimise the patient’s pain. Patients should be discouraged from using toothpastes and mouthwashes that contain sodium lauryl sulphate (5). The utilization of SLS free products is a simple measure that may decrease the number of outbreaks and/or minimize the pain, as well as the severity of their mouth ulcers that develop.

Available products: 

• Copper sulphate and iodine

• Chlorhexidine Gluconate

• Listerine (benzoic acid; cineole; ethanol; thymol; zinc chloride)

Copper sulphate and iodine

Some Over-The-Counter (OTC) aphthous ulcer medications contain copper sulphate and iodine that serve as antibacterial agents. These products can help to prevent a secondary bacterial infection from forming in the ulcerated lesion.

• They are intended to control microbial contamination and secondary infection (7). Some products may also provide symptomatic treatment of RAS 

• Long term use may result in extrinsic staining of teeth and fillings (chlorhexidine especially)

• A bitter taste usually results and formulations also cause brown staining of the teeth and tongue

Chlorhexidine gluconate (a collagenase inhibitor) is available as a prescription anti-bacterial mouthwash (5). Its use has been shown to accelerate healing of aphthous ulceration. A regimen of rinsing (and spitting out) three times a day has been studied and found to provide some benefit. However, the use of chlorhexidine has not been shown to lessen the pain that accompanies aphthous ulcers.

The following is a suggested regimen:

• Chlorhexidine gluconate alone as chlorhexidine 0.2% mouthwash, 10 mL held in the mouth for 1 minute, 8 to 12-hourly while the ulcers are present (6)

OR

• Chlorhexidine gluconate in a combination product (e.g. Difflam-C Anti-inflammatory Antiseptic Solution: Benzydamine hydrochloride 22.5 mg/15 mL (0.15% w/v), chlorhexidine gluconate 18 mg/15 mL (0.12% w/v) and ethanol 1.05 g/15 mL.) The recommended adult dosage is 15 mL (approx. 1 tablespoon) swirled in mouth for 30 seconds every 1.5-3 hours as needed for a maximum of 7 days. Solution can be used undiluted unless burning or stinging occurs and should be expectorated after use. Teeth should be brushed before use (11). 

 Listerine

Documented patient experience has suggested that Listerine (or one of its generic equivalents) several times a day is beneficial (5). Listerine (Pfizer Inc., New York, NY;800/223-0182) was evaluated in a 6-month double-blind study and was found  to reduce the duration and severity of oral aphthae when used twice a day (1).

c)      Topical analgesic sprays or rinses (5,6,8,9,11)

Analgesic and protective ointments, pastes, gels and aerosol sprays can be used to provide pain relief. Spray-based corticosteroids such as betamethasone and beclomethasone spray formulations are an alternative to topical preparations when the area that needs treatment is large (9). 

These agents are optimal for use in the posterior part of the mouth, as stronger analgesic preparations can affect the laryngeal reflexes. 

 Available products

•  Benzydamine hydrochloride

•  Milk of Magnesia and Benadryl Allergy liquid 

Benzydamine hydrochloride anti-inflammatory throat spray can be used to reduce discomfort. Dose: Adults, children > 12 yrs: 4-8 sprays onto sore/inflamed area; swallow gently; repeat every 1.5-3 hours as necessary; max. duration 7 days. Children 6-12 years: 4 sprays as above (11).

Milk of Magnesia and Benadryl Allergy liquid (in a 50:50 mixture) has been found useful by some patients. Dose: swish a teaspoonful over aphthous ulcers (and then expectorate) four to six times a day to help to minimize the pain.

d)      Topical/ Local Anaesthetics and Analgesics (5,6,8,9,11)

Aphthous ulcers can be very painful to the touch, so much so that they may limit the individuals oral activities.

Available OTC agents:

• Benzocaine

• benzoin tincture

• lignocaine (lidocaine)

• camphor

• phenol

These products can be useful in minimizing the degree to which aphthous interfere with normal daily activities. Some manufacturers incorporate their anaesthetics into pastes that can create a protective barrier film over a aphthous ulcer's surface.

A suitable anesthetic includes 2% lignocaine gel every 3 hours, which may be effective for symptomatic relief.  It can also be diluted as a rinse. It is more effective in severe cases of RAS. However, it should be noted that long-term use of topical lignocaine (lidocaine) is not advisable due to concerns of absorption.

e)      Cleansing products (5,11)

The accumulation of debris on the surface of an aphthous ulcer can have an inhibitory effect on healing. A number of OTC products can be found that aid in the removal of this debris. Some of the active ingredients commonly found in these types of products include: carbamide peroxide, hydrogen peroxide, and sodium perborate monohydrate.

Products include:

• Peroxyl Oral Cleanser Solution (active ingredient: hydroxyl peroxide)

• Amosan (active ingredient: sodium perborate)

f)        Herbal Remedies

Herbal sedatives such as chickweed and violet and the herbal medicine rockrose, are believed to reduce anxiety, and have been suggested as treatments for aphthous ulcers.

g)      Topical Antibiotics

Topical antibiotics are highly effective in reducing the pain associated with  severe ulceration. They are known to reduce ulcer size, duration and pain because of their ability to reduce not only secondary infection but also to inhibit collagenase activity. Adverse effects include dysgeusia, skin reactions, thrush, angular cheilosis and burning and soreness of the throat has been reported if tetracycline when used for more than five days

Disadvantages of using broad-spectrum antibiotics for the treatment of RAUs include:

• Encouragement of growth of resistant organisms.

• An increased risk of hypersensitivity reactions

• Local secondary infection by opportunists such as Candida species 

 Formulations include:

• Tetracycline

• Tetracycline /chlortetracycline

Tetracycline

Clinical studies at the National Institute of Dental Research have found that rinsing with the antibiotic tetracycline several times a day can reduce the pain associated with aphthous ulcers and also accelerate healing. 

It is recommended that patients swish mouth with tetracycline (dissolved soluble tetracycline capsule 250 mg in 5–10 mL water) for up to five minutes (and then spit it out) several times a day. However, the use of tetracycline rinse has not been shown to reduce the rate of recurrence of aphthous ulcers. 

h)      Anti-inflammatory medicines

Anti-inflammatory medicines help to minimise the progress of a RAU. The less developed an ulceration is the more quickly it can heal.

Products available:

• Aphthasol (not in Australia)

• Kenalog (triamcinolone acetonide)

• Lidex (fluocinonide)

• Diprolene (betamethasone)

• Temovate (clobetasol)

Aphthasol (amlexanox) (5) is a relatively new prescription item indicated for treatment of  recurrent minor aphthous ulcers. It quite possibly offers the most effective solution for patients. Aphthasol has been found to have both anti-allergic and anti-inflammatory properties, although the precise mechanism of action is unknown. Research studies have demonstrated that the use of Aphthasol can both accelerate the resolution of pain and accelerate RAU healing. The use of Aphthasol (continuously or intermittently) has not been shown to reduce the rate of recurrence of aphthous ulcers.

One study evaluated participants on day three of their RAU’s presence. At this point 44% of the participants using Aphthasol vs. 20% of those not using this product reported complete resolution of pain from their aphthous ulcers. 21% of the participants using Aphthasol vs. 8% not using this product reported complete ulcer healing.

Aphthasol is a paste. When it is applied it forms a film over the ulcer, thereby holding the product's active ingredient in place and also to covering and protecting the  ulcerated surface. The manufacturer recommends applying Aphthasol directly to a person's aphthous ulcers four times daily (after each meal and before bedtime) until healing has occurred.

Kenalog (triamcinolone acetonide, currently unavailable in Australia) is a synthetic corticosteroid . Corticosteroids have anti-inflammatory properties and therefore help to limit the full extent to which ulceration will progress. The Orabase component of this product is a paste designed to adhere to the surface of oral lesions. The use of Kenalog has not been shown to decrease the rate of recurrence of aphthous ulcers.

Fluocinonide (Lidex), betamethasone (Diprolene), and clobetasol (Temovate) are other corticosteroids that are used in similar fashion in the treatment of RAUs. However, a problem associated with the use of topical corticosteroids in general is that they can facilitate the overgrowth of Candida (an oral yeast-like fungus presenting as a secondary infection) (5). 

i)        Topical corticosteroids and Potent Corticosteroids

Corticosteroids are effective drugs in the treatment of RAS, however they have no role in the prevention of recurrence of aphthous ulcers. Response is variable, and there are some individuals who gain little or no relief from their use. After investigation for underlying disease states or reasons such as malnutrition, topical corticosteroids have yielded results in RAUs (3,13).

Corticosteroids exhibit two modes of action;

• Their anti-inflammatory action modifies ulceration progression at all stages and reduce the discomfort experienced by patients.

• Steroidal effect, i.e. the specific blocking effect of the T lymphocyte - epithelial cell interaction, is much more important in the present context. Since the concentration of sensitised lymphocytes occurs before and during the early stages of oral ulceration, it follows that the drugs exert their maximum effect at this time.

There is minimal risk of adrenal suppression provided that the recommended dose (four times daily) is adhered to.

Topical preparations

Potent topical corticosteroid preparations (not all available in Australia)

• triamcinolone acetonide

• betamethasone valerate (mouthwash)

• beclomethasone dipropionate (spray)

• betamethasone dipropionate (spray)

• hydrocortisone hemisuccinate

• triamcinolone acetonide +/- chlortetracycline

• betamethasone sodium

Products Available:

• triamcinolone acetonide 0.1% paste, applied topically every 8 hours (available in Australia)

• betamethasone valerate 0.05% ointment, applied topically every 8 hours (6)

• hydrocortisone hemisuccinate (2.5mg pellets) with triamcinolone acetonide (in adhesive paste containing 0.1% steroid) 

• betamethasone sodium phosphate rinse (dissolve 0.5 mg in 5 mL of water and rinse for 2–3 min)

• beclometasone diproprionate, aerosol ( 100 µg/puff)

• betamethasone propionate aerosol 

High potency topical corticosteroid preparations

These preparations are used in severe RAS unresponsive the hydrocortisone hemisuccinate and triamcinolone acetonide. However, it should be noted that prolonged use of potent topical corticosteroids carries a risk of systemic absorption and associated adverse effects; it may also predispose to oral candidiasis.

Products Available:

• clobetasol 0.05% in orabase (1: 1)

• fluocinonide 0.05% in orabase (1: 1)

Systemic preparations

• prednisolone +/- azathioprine

For the severe and constantly recurring ulcerations, topical management of RAU may not be enough.

Available products: 

• prednisolone 25 mg orally, daily for 5 days for major aphthous ulceration only (6)

Prednisolone (combination of gels and rinses) is started at 1.0 mg/kg a day as a single dose in patients with severe RAU and should be tapered after 1 to 2 weeks. Long term adverse effects include depression, hyper-glycemia, lipodystrophy, moon faces and hypothalamic-pituitary-adrenal axis suppression. Prednisolone can also combined with another immunosuppressive agent, azathioprine, to reduce the dosage of prednisone required to provide effective treatment. 

Azathioprine

• can be used in combination with systemic or topical steroid therapy.

• Adverse effects include thrombocytopenia, leukopenia, secondary infections, anemia, nausea, vomiting, anorexia, diarrhoea, and lymphoreticular and other malignancies after long-term therapy

Note: intralesional injections may also be used.

k)      Future Advances- immunomodulating and anti-inflammatory drugs

Levamisole

• Levamisole is an immunopotentiating agent indicated when topical corticosteroids fail to improve ulcers.

• Levamisole 50mg three times daily has been reported to reduce the frequency and duration of RAS anc can lead to remissions of up to 6 months. However, the possibility of side effects (nausea, hyperosmia, dysgeusia, and agranulocytosis) discourage its use.

•  Levamisole has shown variable efficacy in reducing ulcer frequency and duration in patients with minor RAU (7).  It significantly reduce pain intensity and ulcer number, duration, and frequency in many studies

• Levamisole was well tolerated in a majority of the patients (4).frequent adverse effects were dysgeusia (21%) and nausea (16%).

Thalidomide

• Is a TNF[alpha] inhibitor that has anti-inflammatory effects. It inhibits the production of various cytokines (e.g. tumor necrosis factor-alpha).

• Thalidomide is effective but, because of its toxicity and cost, should be used only as an alternative to oral corticosteroids (7)

• Thalidomide has been indicated for severe RAS which has failed to respond to other treatment modalities

• It also been advocated for use in HIV-associated oral ulceration. However, its use is limited because of teratogenic and other adverse effects (e.g. irreversible polyneuropathy).