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The Best Treatment For Aphthous Ulcers
An evidence-based study of the literature R. Fernandes, T. Tuckey, P. Lam, S. Allidina, S. Sharifi and D. Nia Abstract
This evidence-based study of the literature set out to examine the various treatment options for recurrent aphthous stomatitis (RAS) and identify the best therapeutic choice for managing the condition. Currently, treatment options include symptomatic relief of the canker sore using topical agents or antibiotics, or non-intervention treatment wherein the ulcer heals on its own. The review is based on literature from a search of several electronic databases including references from the potential articles obtained, as well as information obtained from dental textbooks and an oral pathologist. A total of 69 randomized control trials (RCTs) were deemed relevant and were critically appraised according to an “efficacy checklist”. Six studies met the criteria of scoring >13/15 on the checklist with statistically significant results and potential applications in clinical treatment. The therapeutic options investigated included 5% amlexanox, penicillin G, silver-nitrate cautery and doxymycine. Benefits versus risk for each treatment option were examined, and the best form of therapy was based on an agent that would encompass reduction in pain and healing time and prevent further recurrences. Based on these criteria, 5% amlexanox was determined to be the most effective form of treatment for RAS.
MeSH Key Words: Aphthous stomatides; Aphthous stomatitis; Recurrent Aphthous Stomatitis; Stomatides,
Aphthous; Aphthae; Ulcer, Aphthous; Aphthous ulcer; Aphthous ulcers; Aphthous; Ulcers, Aphthous; Canker sore;
Canker sores; Sore, Canker; Sores, Canker; Periadenitis mucosa necrotica recurrence
weeks.1 Herpetiform ulcers are the least common stomatitis (RAS), commonly referred to as canker variety and account for only 5-10% of cases.2,3 sores, are inflammatory lesions of the mucous lining of the mouth which may involve the cheeks, keratinized mucosa unlike aphthae minor and gums, tongue, lips, and roof or floor of the mouth. major which are limited to non-keratinized It is usually painful and associated with redness, swelling, and occasional bleeding from the affected area(s). Manifestation of the disease can common form of oral ulcerative diseases and range from mild to severe and, in extreme cases, affects an estimated 15-20% of the population even hinder a person’s ability to ingest foods, worldwide. In some populations, the prevalence thereby making the person susceptible to has been documented as being as high as 50-66%5 and it is especially common in North America.3 These aphthae can also occur as widespread several factors are suspected including genetics, lesions in association with systemic diseases stress, nutritional deficiencies, diet, hormonal including Behcet’s syndrome, and gastrointestinal changes, and immunological disorders. 1,2,5 Due to malabsorption disorders like Crohn's and Celiac the indeterminate etiology of the disease, it is diseases. 1,3,6 It is unclear whether these difficult to find a definitive cure and current presentations are manifestations of the underlying treatments are aimed towards ameliorating the disease or represent a separate oral disorder.3 There are 3 clinical presentations of RAS: goals being to decrease pain, healing time, number aphthous minor, aphthous major and herpetiform and size of the ulcer, and to increase disease-free ulcers. Aphthous minor are the most common periods. Current treatment options include topical and account for 80-95% of all RAS lesions. They are white ulcerative lesions that may be single or corticosteroids, cauterization, antibiotics, mouth multiple and round or oval.2,3 Two to eight crops rinses containing active enzymes, laser treatments of lesions occur per year, lasting 7 to 14 days and and combination therapy. Given the prevalence of then heal without scars.4 Aphthous major, RAS, primary care physicians and dentists should become familiar with its presentation and characterized by larger lesions with 1-2 lesions management and be able to offer therapeutic occurring at a time. These are more common in options that meet their patients’ needs. The report serves as an educational medium for health associated with severe pain, lasting 6 or more professionals, so that they may become equipped with the knowledge to manage patients who oral pathology were consulted, as was the expert present with RAS. Since aphthous minor is the most prevalent form of RAS, this report focuses Determination of Relevance using Validity
specifically on its treatment options. The findings Instruments
of this report may not be generalizable to patients In the abstract stage, queries were limited with major or herpetic aphthae or those with to Randomized Controlled Trials and this process forms of RAS that are manifestations of systemic yielded 69 articles in Pubmed, 17 in Ovid Medline disorders. For other forms of RAS, therapy should and none in Cochrane. Following the elimination be individually tailored to the patient depending of duplicate articles (overlapping articles within on the severity of the ulcer and the patient’s health. the electronic databases), a total of 69 articles remained. A search of the references within these articles was also conducted, on the basis of titles, A systematic literature search was employed to but no articles were retrieved in this manner. identify, select, critically appraise and utilize Of these 69 articles, 40 were eliminated based on titles – these articles either dealt with Search Strategy
non-healthy populations (i.e. people with AIDS) MeSH was initially used to expand on the or RAS as a manifestation of a systemic disorder. vocabulary, so as to conduct a more extensive The remaining 29 articles were retrieved and search on the topic. The following terms were analyzed for relevance. Articles were considered used in the searches: Aphthous stomatides; relevant if they met the following criteria: 1) primary research; 2) the best evidence as set by the stomatides; Aphthae; Aphthous ulcer; Aphthous classification system of the Canadian Task Force ulcers; Aphthous; Canker Sore; Canker Sores; on the Periodic Health Examination (CFTPHE)7; Apthous ulcer; treatment/therapy for Aphthous and 3) a score of >13/15 on the checklist to ulcer(s) and management of/managing aphthous assess the efficacy of a therapy or intervention ulcers. To locate relevant articles, several (Table 1)8. Articles with inconclusive or electronic databases were used: Pubmed (1966 – conflicting evidence were disregarded, as were present), Ovid Medline (1966 – present) and articles with poor design or those using an Cochrane, which yielded 2546, 505 and 12 articles alternate therapy as a control (Appendix 1). A respectively. The next stage was to limit the search total of 6 RCTs met all criteria and were further to studies published in English that dealt with human subjects of all ages and this decreased the number of potentially relevant articles to 1466 in investigated penicillin G, 1 investigated silver Pubmed while the others remained unchanged. In nitrate cautery and the last investigated addition to using online databases, textbooks in Table 1: Checklist to Assess Evidence of Efficacy of Therapy or Prevention8
Was the study ethical? (1 point)
Was a strong design used asess efficacy? (1)
Were outcomes (benefits and harms) validly and reliably measured? (1) What were the results? Was the treatment effect large enough to be clinically important? (1) Was the estimate of the treatment effect beyond chance and relatively precise? (1) If the findings were “no difference” was the power of the study 80% or better? (1) Was the assignment of patients to treatments randomized? (1) Were all patients who entered the trial properly accounted for and attributed at its conclusion? ¾ Was loss to follow-up less than 20% and balanced between test and controls?(1/2) ¾ Were patients analyzed in the groups to which they were randomized? (1/2) Was the study of sufficient duration? (1) Were patients, health workers, and study personnel “blind” to treatment? (1) Were groups similar at the start of the trial? (1) Aside from the experimental intervention, were the groups treated equally? (1) Was care received outside the study identified and controlled for? (1) Will the results help in caring for your patients? (1) Were all clinically important outcomes considered? (1) Are the likely benefits of treatment worth the potential harms and costs? (1) Results
Table 2: Studies investigating treatment of RAS
Study
Subjects
Treatment Method
Effect(s) observed
[Total (final)]
publication
Binnie and
Tx: 5% Amlexanox oral paste
Control: placebo (vehicle)
-After 3 days, a significant difference in Generally healthy, history ulcers healing or study ending -No unusual or unexpected adverse reactions reported Tx: of 5% Amlexanox oral
-↓ healing time by 0.8 days compared to Generally healthy, history Control: placebo (vehicle) and
Tx: 150 mg doxymycine + 1ml
Control: 150 mg calcii
1cryo (n=16) Mean pain level VAS recorded Tx: topical 50mg penicillin G
-Significant acceleration of healing and pain Generally healthy, history potassium troches (Cankercillin) relief of minor RAU (n=31)
Control: placebo (n=33), no tx
Tx: silver nitrate sticks gently
-Significant ↓ pain 1 day after procedure Generally healthy, history cauterization (n=47) Control: placebo (n=38)
-No significant difference in time to heal Tx: 0.5cm of 5% Amlexanox
-By day 3, 35% of prodromal group had an paste applied 4x/day beginning: ulcer present compared with 97% in placebo Generally healthy, history 1. within 12h of onset of -Prodromal tx ↓ ulcer size and extent by ulceration to see if healing could -↓ healing time by 4.1 days if used at Control: placebo
-Tx at onset of prodrome rather than at ulceration = 71% ↓ in extent of ulceration and a 35% ↓ in max pain -Side effects were mild and transient (e.g, dry mouth and numbness at application site) -Product considered easy to use Four studies investigated the drugs’ effects on pain and healing times. Three of these examined thermographic imagers, and alongside the compliance 5% Amlexanox9,10,11 and these studies showed a issue of applying the paste 4 times per day, diagnosing significant (p<0.05) reduction in pain and healing and treating the prodromal ulcer is difficult and the time when Aphtheal was applied to the ulcer 4 times treatment is unlikely to yield the same results as seen a day from ulcer onset until healing. It was further in the study. Furthermore, the reduction in pain and demonstrated that application of 5% Amlexanox healing time is not necessarily clinically significant. during the prodromal stage significantly reduced ulcer Alidaee and others 14 found healing to take 7-10 days recurrence11. The fourth study12 examined Penicillin with pain subsiding after 4-5 days; however, with G and showed a significant decrease in pain and Amlexanox treatment, median healing time was only healing time when it was applied 4 times daily until reduced by 1.6 days and the median time to complete complete healing of the ulcer. None of the subjects in pain relief was decreased by only 1.3 days – results any of these experiments showed any significant side which are not necessarily clinically significant. Further, Murray11 found that 5% Amlexanox lead to Two studies investigated the drug’s effect on pain resolution in 83% of subjects compared with pain only: Ylikontiola and others13 investigated the 73% of those using a vehicle, indicating that simply effects of Doxymycine and Alidaee and others14 covering the lesion provided some benefit to the investigated the effects of silver nitrate cauterization. Both drugs significantly reduced pain without any In conclusion, due to the unknown etiology significant reduction in healing time. The reduction of of RAS most of the treatment is therapeutic. pain seen with silver nitrate is rapid and lasts for the Literature shows that aphthous ulcers are best treated duration of the lesion; however it was perhaps due to with 5% Amlexanox as it decreases healing time and the destruction of local nerve endings. 14 Furthermore, pain and prevents recurrences if applied in the adverse effects have been reported with silver nitrate prodromal stage. The effectiveness of treatment, such as argyria, mucocutaneous reactions15 and however, is not clinically significant since pain relief tattooing of the mucosa.16 These side effects make and healing time is accelerated by only 1.3 and 1.6 silver nitrate an unlikely choice of treatment especially days respectively and since a vehicle also reduces pain. since the healing time is not affected by the The effectiveness of prevention showed statistically significant results; however, diagnosis of the prodromal stage is subjective, while the objective Discussion
thermographic imaging is impractical and thus not According to this literature review, the best clinically utilizable. Therefore, based upon the treatment for minor RAS is 5% Amlexanox. It is the inherent difficulties associated with treatment of only agent that has a “triple action” in the form of aphthous ulcers, the clinician should individualize preventing recurrences, decreasing healing time and treatment to each patient by considering a number of accelerating pain resolution. Penicillin G only relevant factors, including the potential psychological reduced pain and healing time, while doxymycine and benefits of treatment, the degree of patient discomfort experienced, the probability of patient Amlexanox has only mild and transient side compliance with required application procedures and effects.11 While the results are statistically significant, trade-offs between the enhanced rate of recovery and they do not necessarily correlate well as being the economic burden of purchasing the treatment. clinically useful since the prodromal stage (the stage at which the drug was shown to have the “triple action” effect) is hard to determine. The prodromal stage is Acknowledgements: The authors wish to thank Dr. Iona characterized as a burning or pricking sensation 24 - Leong, Department of Oral Pathology and Oral Medicine, 48 hours before the onset of the ulcer but it is not Faculty of Dentistry, University of Toronto for her guidance in easily identified by all patients. In Murray’s study,11 determining which treatments for aphthous ulcers were clinically the prodromal stage was determined through subjective measures of sensation to predict the ulcer as well as the use of a thermographic imager as confirmation. Thermographically active data meant a References
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Articles
Reason for exclusion
Chadwick and others 1991; Drinnan and Fischman 1978; Fridh Did not score ≥13/15 on efficacy checklist and Koch 1999; Garnick and others 1998; Hodosh and others 2004; Matthews and others 1987; Miles and others 1993; Muzio and others 2001; Olsen and Silverman 1978; Saxen and others 1997 Atik and others 2003; Brice and others 1997; Jacobson and others Inconclusive evidence (statistically insignificant) 1997; Jacobson and others 2001; Jenkins and others 1984; Revuz and others 1990; Ricer 1989; Taylor and others 1993; Cree and others 1978 Lu Muzio and others 2001; Saxen and others 1997 Other variables were being compared e.g. use of adhesive / delivery vehicle Used an existing therapy as control (rather than placebo or Pedersen and others 1990; Pedersen and others 1990 Did not have washout period to rule out lingering effects of 1st treatment
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