Amlexanox for the Treatment of Recurrent Aphthous Ulcers

Juliette Bell


Clin Drug Invest. 2005;25(9):555-564. 

In This Article


Recurrent aphthous ulcer (RAU) is the most prevalent oral mucosal disease in humans, estimated to affect between 5% and 50% of the general population. The minor manifestation of the condition is the most common and is characterised by small, shallow, round or oval lesions that are surrounded by a raised erythematous halo and are covered by a grey-white pseudomembrane. Appropriate management of patients with this condition is largely symptomatic and should focus on reducing ulcer duration, relieving pain and reducing or preventing ulcer recurrence. Amlexanox is a novel anti-inflammatory and anti-allergic agent that has been evaluated for the treatment of RAU in a series of robust clinical trials. After a 100mg dose of 5% amlexanox topical paste, applied directly to the lesion, the maximum serum concentration of the drug was 120 ng/mL, which was achieved 2.4 hours after application. Steady-state concentrations were achieved within 1 week of starting four times daily dosing and there was no evidence of accumulation. In terms of efficacy, application of 5% amlexanox topical paste was shown to consistently and significantly accelerate complete ulcer healing and the time to resolution of pain across four large efficacy studies. Significantly more patients had completely healed ulcers from day 3 (compared with no treatment) and day 4 (compared with vehicle). Healing was mirrored by an improvement in pain: significantly more patients had complete resolution of pain from day 2 (compared with no treatment) and day 3 (compared with vehicle). Overall, amlexanox was well tolerated, with a low frequency of adverse effects. In the oral application studies, adverse effects that were considered by investigators to be potentially related to the study treatment occurred in 2.4% and 2.1% of 5% amlexanox and vehicle recipients, respectively. These effects were mainly local and were all classed as mild to moderate in severity, with the exception of one case of severe stinging in the vehicle treatment group. Furthermore, the incidence of dermal irritation and sensitisation was very low with amlexanox. These findings suggest that 5% amlexanox topical paste is a useful and well tolerated therapeutic option for the treatment of RAU.


Recurrent aphthous ulcer (RAU) is the most prevalent oral mucosal disease in humans, estimated to affect between 5% and 50% of the general population, although the true prevalence is probably greater, given that active lesions may not be present at the time of examination.[1,2,3] This disorder is also commonly referred to as canker sores, recurrent aphthous stomatitis, recurrent oral ulcers and simple or complex aphthosis.

RAUs are characterised by round, clearly defined, painful lesions covered by a fibromembranous slough with an erythematous halo.[1,4] It generally first presents in childhood or adolescence and then continues into adulthood.[5] Interestingly, cross-sectional studies indicate that females and individuals in higher socioeconomic classes have a higher prevalence and severity of this disease.[2]

RAUs have been classified into three subtypes: minor aphthous ulcers, major aphthous ulcers and herpetiform ulcers ( Table I ).[2,6,7,8,9,10] Minor RAU is the most common manifestation of the disorder, occurring in 75–80% of patients with RAU. This is characterised by shallow round or oval lesions of <10mm in diameter that are surrounded by a raised erythematous halo and covered by a grey-white pseudomembrane. These moderately painful ulcers generally appear on the non-keratinised oral mucosa (that is, the labial and buccal mucosa and the floor of the mouth) and resolve within 7–14 days without scarring. Patients generally notice a burning or tingling at the ulcer site as the lesion begins to develop. In this prodromal stage, which lasts around 24 hours, the epithelium is infiltrated with mononuclear cells and oedema develops. The lesion then becomes increasingly painful as macules and papules with a surrounding erythematous halo develop. This is known as the pre-ulcerative stage and generally occurs in the first 18–72 hours of lesion development. The ulcerative stage itself may last for a number of days, while the pseudomembrane that covers the wound lessens the pain associated with the lesion. Finally, the ulcer is covered by epithelium and wound healing occurs.[11]Table I . Classification of recurrent aphthous ulcers (RAUs)[7,8]Table II . Summary of amlexanox clinical trials[77,78]

Major RAU is a more severe form of RAU, affecting approximately 10% of patients with RAU. Lesions are generally deeper than those observed in minor RAU, often exceed 10mm in diameter and can be very painful. Major RAU lesions generally take several weeks to heal and often leave a scar.[2,6,7,8,10]

Despite the nomenclature of herpetiform ulcers, these multiple clusters of small lesions that occur throughout the oral cavity are not related to herpes simplex virus. Although the individual ulcers are between 2 and 3mm in diameter, these can cluster together to form large, irregular, plaqueform lesions that generally heal with scarring within 7–10 days. Approximately 10% of patients presenting with RAU have the herpetiform manifestation.[2,6,7,8,10]

RAU can also be classified as simple aphthosis or complex aphthosis. The simple manifestation is characterised by short-lived episodes involving a few lesions that heal quickly with minimal pain. These are limited to the oral cavity. Conversely, complex aphthosis is a more disabling state, characterised by numerous and large lesions, continued ulceration and marked pain. Furthermore, lesions may occur in the genital or perianal regions.[1,12]

The underlying aetiology of RAU is poorly understood, possibly because most patients with the condition are otherwise well. Pathogenesis is likely to be multifactorial, with potential predisposing factors including altered immunoregulatory balance,[13,14,15,16,17] infection with bacteria[8] or viruses such as herpes simplex, varicella zoster and Epstein-Barr,[17,18,19,20] genetic disposition,[2,17,21] haematological deficiencies in iron, folate, zinc or vitamin B,[17,22,23,24,25] and food hypersensitivity and allergies.[26] Trauma, including injections, sharp foods, tooth brushing and orthodontic treatment, may also play a precipitating role in the development of RAU[27] as may emotional or environment stress.[28,29] Interestingly, smoking appears to reduce the likelihood of RAU, with the condition sometimes occurring or recurring in individuals who have ceased smoking.[30]

Several systemic diseases are also associated with an increase in the prevalence or severity of RAU. RAU-like lesions are common in Behçet's disease,[31,32] HIV infection,[33,34,35,36] Crohn's disease[37,38] and, to a lesser extent, ulcerative colitis.[39,40] Another gastrointestinal disease associated with RAU is coeliac disease (also known as gluten-sensitive enteropathy), possibly due to malabsorption of B vitamins, folate and iron.[23,41,42] Other systemic disorders with a potential link to RAU include mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome;[1] periodic fever, aphthosis, pharyngitis, adenitis (PFAPA) syndrome;[43,44] cyclic neutropenia;[45] and immunoglobulin A (IgA) deficiency.[46]