简介：本文献循证研究的目的在于从纷繁的复发性阿弗他口腔溃疡的治疗方法中，鉴定出对其治疗的最佳方法。目前，治疗方法中有减轻症状的局部制剂和抗生素，或让口腔溃疡自然愈合的自然疗法，本综述的文献选择于几个大的电子数据库中的研究论文，同时也有教科书及口腔病理专家的材料。有69个随机双盲研究（RCTs），其中6个符合评价标准（≥13/15），即具有统计学意义和临床应用价值，它们是5%氨来呫诺、青霉素G、硝酸银灼烧和四环素。通过每种治疗方法的利弊比较，最好的治疗方法应该兼有减轻疼痛、促进愈合和防止复发的作用。基于上述标准：5%氨来呫诺是所有治疗RAS的方法中最好的一个。 The Best Treatment For Aphthous UlcersAn evidence-based study of the literatureR. Fernandes, T. Tuckey, P. Lam, S. Allidina, S. Sharifi and D. Nia 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　　Aphthous ulcers or recurrent aphthous stomatitis (RAS), commonly referred to as canker sores, are inflammatory lesions of the mucous lining of the mouth which may involve the cheeks, gums, tongue, lips, and roof or floor of the mouth. It is usually painful and associated with redness, swelling, and occasional bleeding from the affected area(s). Manifestation of the disease can range from mild to severe and, in extreme cases, even hinder a person’s ability to ingest foods, thereby making the person susceptible to malnutrition.1　　 The cause of RAS is unknown, although several factors are suspected including genetics, stress, nutritional deficiencies, diet, hormonal changes, and immunological disorders. 1,2,5 Due to the indeterminate etiology of the disease, it is difficult to find a definitive cure and current treatments are aimed towards ameliorating the symptoms.　　 There are 3 clinical presentations of RAS: aphthous minor, aphthous major and herpetiform ulcers. Aphthous minor are the most common and account for 80-95% of all RAS lesions. They are white ulcerative lesions that may be single or multiple and round or oval.2,3 Two to eight crops of lesions occur per year, lasting 7 to 14 days and then heal without scars.4 Aphthous major, accounts for 10-15% of RAS cases and is characterized by larger lesions with 1-2 lesions occurring at a time. These are more common in the immunodeficient population, and are associated with severe pain, lasting 6 or more weeks.1 Herpetiform ulcers are the least common variety and account for only 5-10% of cases.2,3 They appear on both non-keratinized and keratinized mucosa unlike aphthae minor and major which are limited to non-keratinized mucosa.3　　 Aphthous minor is amongst the most common form of oral ulcerative diseases and affects an estimated 15-20% of the population worldwide. In some populations, the prevalence 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 lesions in association with systemic diseases including Behcet’s syndrome, and gastrointestinal malabsorption disorders like Crohns and Celiac diseases. 1,3,6 It is unclear whether these presentations are manifestations of the underlying disease or represent a separate oral disorder.3　　 Treatment for RAS is symptomatic; the goals being to decrease pain, healing time, number and size of the ulcer, and to increase disease-free periods. Current treatment options include topical agents, systemic and topical steroids, corticosteroids, cauterization, antibiotics, mouth rinses containing active enzymes, laser treatments and combination therapy. Given the prevalence ofRAS, primary care physicians and dentists should become familiar with its presentation and management and be able to offer therapeutic options that meet their patients’ needs. The reportserves as an educational medium for health professionals, so that they may become equipped with the knowledge to manage patients who present with RAS. Since aphthous minor is the most prevalent form of RAS, this report focuses specifically on its treatment options. The findings of this report may not be generalizable to patients with major or herpetic aphthae or those with forms of RAS that are manifestations of systemic disorders. For other forms of RAS, therapy should be individually tailored to the patient depending on the severity of the ulcer and the patient’s health.Methods　　 A systematic literature search was employed to identify, select, critically appraise and utilize relevant studies.Search Strategy　　 MeSH was initially used to expand on the vocabulary, so as to conduct a more extensive search on the topic. The following terms were used in the searches: Aphthous stomatides; Recurrent aphthous stomatitis; Aphthous stomatides; Aphthae; Aphthous ulcer; Aphthous ulcers; Aphthous; Canker Sore; Canker Sores; Apthous ulcer; treatment/therapy for Aphthous ulcer(s) and management of/managing aphthous ulcers. To locate relevant articles, several electronic databases were used: Pubmed (1966 –present), Ovid Medline (1966 – present) and Cochrane, which yielded 2546, 505 and 12 articles respectively. The next stage was to limit the search 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 Pubmed while the others remained unchanged. In addition to using online databases, textbooks in oral pathology were consulted, as was the expert opinion of an oral pathologist.Determination of Relevance using Validity Instruments　　 In the abstract stage, queries were limited to Randomized Controlled Trials and this process yielded 69 articles in Pubmed, 17 in Ovid Medline and none in Cochrane. Following the elimination of duplicate articles (overlapping articles within 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, but no articles were retrieved in this manner. 13/15 on the checklist to assess the efficacy of a therapy or intervention (Table 1)8. Articles with inconclusive or conflicting evidence were disregarded, as were articles with poor design or those using an alternate therapy as a control (Appendix 1). A total of 6 RCTs met all criteria and were further analyzed. From the 6 relevant studies 3 investigated 5% Amlexanox (Aphtheal), 1 investigated penicillin G, 1 investigated silver nitrate cautery and the last investigated Doxymycine (Table 2).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)Are the results of the study valid?　　 • Was the assignment of patients to treatments randomized? (1)　　 • Were all patients who entered the trial properly accounted for and attributed at its conclusion?􀂾 　　Was loss to follow-up less than 20% and balanced between test and controls?(1/2)􀂾 　　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)                                                  ResultsTable 2: Studies investigating treatment of RAS StudyDate ofpublication Subjects[Total (final)] Treatment Method Effect(s) observed Binnie and others, 1997 Adults ≥ 18 (mean 27.5) 48% male, 86% Caucasian Generally healthy, history of minor RAU [1133(1124)] Tx: 5% Amlexanox oral paste Control: placebo (vehicle) Evaluated daily until 1st of ulcers healing or study ending -↓ healing time by 1.6 days-↓ time to pain relief by 1.3 days-After 3 days, a significant difference in healing (21% vs. 8%) and complete pain resolution (44% vs 20%)-Vehicle may provide some benefit-No unusual or unexpected adverse reactions reported Khandwala and others, 1997 Adults ≥ 18 (mean 28.6) 633 male, 702 femaleGenerally healthy, history of minor RAU [1335 (1295)] Tx: of 5% Amlexanox oral paste Control: placebo (vehicle) and no treatment “Dab” applied to ulcers 4x/day until ulcers healed or study ended -↓ healing time by 0.8 days compared to vehicle and 1.6 days compared to no treatment-Vehicle may provide some benefit Ylikontiola and others, 1997 Adults 28-45 (mean 38) 4 men, 27 women Generally healthy, history of minor RAU [31(31)] Tx: 150 mg doxymycine + 1ml of 0.9% NaCl + 1 drop cryo (n=15)Control: 150 mg calcii gluconase, 1ml 0.9% NaCl, 1cryo (n=16)Mean pain level VAS recorded by pts for 10 days -↓ mean pain level significantly-Adhesive: mean duration 3.5 hrs (not a good adhesive)-All components non-toxic Kerr and others,2003 Adults ≥15 Generally healthy, history of minor RAU [110 (100)] Tx: topical 50mg penicillin G potassium troches (Cankercillin) applied 4x/day for 4 days (n=31)Control: placebo (n=33), no tx(n=36) -Significant acceleration of healing and pain relief-No allergic reactions were observed Alidaee and others, 2005 Adults 16-40 (mean 26) 43 men, 42 women Generally healthy, history of painful RAU [97 (85)] Tx: silver nitrate sticks gently painted on ulcer = chemical cauterization (n=47)Control: placebo (n=38) -Significant ↓ pain 1 day after procedure (70% pain reduction compared to 11% in placebo group)-No significant difference in time to heal-No side effects but-Must be done by trained professional Murray and others, 2005 Adults (mean 37) 60% female, 98% white Generally healthy, history of RAU & associated prodromal symptoms [46 (46)] Tx: 0.5cm of 5% Amlexanox paste applied 4x/day beginning:1. within 12h of onset of prodromal stage to see if ulcer could be prevented2. within 12h of onset of ulceration to see if healing could be improved Control: placebo -By day 3, 35% of prodromal group had an ulcer present compared with 97% in placebo group and 66% in treated ulcer group-Prodromal tx ↓ ulcer size and extent by 84%, pain by 69%, and extent of pain by 85% compared to placebo-↓ healing time by 4.1 days if used at prodromal onset and 0.7 days if used at onset of ulceration-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 VAS: visual analog scaleTx: treatment　　Four studies investigated the drugs’ effects on pain and healing times. Three of these examined 5% Amlexanox9,10,11 and these studies showed a significant (p<0.05) reduction in pain and healing time when Aphtheal was applied to the ulcer 4 times a day from ulcer onset until healing. It was further demonstrated that application of 5% Amlexanox during the prodromal stage significantly reduced ulcer recurrence11. The fourth study12 examined Penicillin G and showed a significant decrease in pain and healing time when it was applied 4 times daily until complete healing of the ulcer. None of the subjects in any of these experiments showed any significant side effects.　　Two studies investigated the drug’s effect on pain only: Ylikontiola and others13 investigated the effects of Doxymycine and Alidaee and others14 investigated the effects of silver nitrate cauterization. Both drugs significantly reduced pain without any significant reduction in healing time. The reduction of pain seen with silver nitrate is rapid and lasts for the duration of the lesion; however it was perhaps due to the destruction of local nerve endings. 14 Furthermore, adverse effects have been reported with silver nitrate such as argyria, mucocutaneous reactions15 and tattooing of the mucosa.16 These side effects make silver nitrate an unlikely choice of treatment especially since the healing time is not affected by the cauterization.Discussion　　According to this literature review, the best treatment for minor RAS is 5% Amlexanox. It is the only agent that has a “triple action” in the form of preventing recurrences, decreasing healing time and accelerating pain resolution. Penicillin G only reduced pain and healing time, while doxymycine and silver nitrate both only reduced pain.　　Amlexanox has only mild and transient side effects.11 While the results are statistically significant, they do not necessarily correlate well as being 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 characterized as a burning or pricking sensation 24 - 48 hours before the onset of the ulcer but it is not easily identified by all patients. In Murray’s study,11 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 surface temperature difference of 0.05°C between the symptomatic mucosa and the contralateral asymptomatic area. In combination with the fact that most offices and homes do not possess thermographic imagers, and alongside the compliance issue of applying the paste 4 times per day, diagnosing and treating the prodromal ulcer is difficult and the treatment is unlikely to yield the same results as seen in the study. Furthermore, the reduction in pain and healing time is not necessarily clinically significant. Alidaee and others 14 found healing to take 7-10 days with pain subsiding after 4-5 days; however, with Amlexanox treatment, median healing time was onlyreduced by 1.6 days and the median time to complete pain relief was decreased by only 1.3 days – results which are not necessarily clinically significant. Further, Murray11 found that 5% Amlexanox lead to pain resolution in 83% of subjects compared with 73% of those using a vehicle, indicating that simply covering the lesion provided some benefit to the patient.　　In conclusion, due to the unknown etiology of RAS most of the treatment is therapeutic. Literature shows that aphthous ulcers are best treated with 5% Amlexanox as it decreases healing time and pain and prevents recurrences if applied in the prodromal stage. The effectiveness of treatment, however, is not clinically significant since pain relief and healing time is accelerated by only 1.3 and 1.6 days respectively and since a vehicle also reduces pain. The effectiveness of prevention showed statistically significant results; however, diagnosis of the prodromal stage is subjective, while the objective thermographic imaging is impractical and thus not clinically utilizable. Therefore, based upon the inherent difficulties associated with treatment of aphthous ulcers, the clinician should individualize treatment to each patient by considering a number of relevant factors, including the potential psychological benefits of treatment, the degree of patient discomfort experienced, the probability of patient compliance with required application procedures and trade-offs between the enhanced rate of recovery and the economic burden of purchasing the treatment.                                                                                                       Acknowledgements: The authors wish to thank Dr. Iona Leong, Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto for her guidance in determining which treatments for aphthous ulcers were clinically useful.                                                                                                       References1. Scully C. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Ass 2003; 134:200-207.52. Scully C and Felix DH. Oral medicine: update for the dental practioner. Aphthous and other common ulcers. Br Dent J 2005; 199(5):259-264.3. Tilliss TSI and McDowell JD. Differential Diagnosis: Is It Herpes or Aphthous? J Contemp Dent Pract 2002; (3)1:001-015.4. Jablonskis Dictionary of Dentistry, 1992. p742.5. Scully C and Porter SR. Recurrent aphthous stomatitis: current concepts of etiology, pathogenesis and management. J Oral Pathol Med 1989; 18(1):21-7.6. Rehberger A, Puspok A, Stallmeister T, Jurecka W, and Wolf K. Crohns disease masquerading as aphthous ulcers. Eur J Dermatol 1998; 8(4):274-6.7. Canadian Task Force for Preventive Health Care. www.ctfphc.org/. Accessed January 10, 2006.8. Leake JL. Community Dentistry Department of Biological and Diagnostic Sciences, Faculty of Dentistry, University of Toronto. Unpublished document. Course notes DEN 300Y1 2005. Thechecklist was adapted from Fletcher RH,Fletcher SW, Wagner EH. Clinical epidemiology. The essentials. 3rd ed. Baltimore: Williams and Wilkins, 1996; and Sackett DL, Richardson WS, Rosenberg W, Haynes RB. Evidence-based medicine: how to practice and teach. EBM. 2nd ed. New York: Churchill Livingstone, 1997.9. Khandwala A, Van Inwegen RG and Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers. Oral Medicine 1997; 83(2):222-30.10. Binnie WB, Curro FA, Khandwala A and Van Inwegen RG. Amlexanox oral paste: a novel treatment that accelerates the healing of aphthous ulcers. Compendium 1997:1116-25.11. Murray B, McGuinness N, Biagioni P, Hyland P and Lamey PJ. A comparative study of the efficacy of Aphtheal in the management of recurrent minor aphthous ulceration. J Oral Pathol Med 2005; 34:413-19.12. Ross Kerr A, Drexel, CA and Spielman AI. The efficacy and safety of 50mg penicillin G potassium troches for recurrent aphthous ulcers. Oral Medicine2003; 96(6):685-94.13. Ylikontiola L, Sorsa T, Hayrinen-Immonen R, and Salo T. Doxymycine-cyanoacrylate treatment of recurrent aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83(3):329-33.14. Alidaee MR, Taheri A, Mansoori P and Ghodsi SZ Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Brit J Dermatl 2005; 153:521-525.15. Murthy P and Laing MR. An unusual severe adverse reaction to silver nitrate cautery for epistaxis in an immunocompromised patient. Rhinology 1996;34:186-7.16. Mayall F and Wild D. A silver tattoo of the nasal mucosa after silver nitrate cautery. J Laryngol Otol 1996; (110):609-610.Appendix 1: List of articles excluded and reasons for exclusion Articles Reason for exclusion Chadwick and others 1991; Drinnan and Fischman 1978; Fridh 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 Did not score ≥13/15 on efficacy checklist Atik and others 2003; Brice and others 1997; Jacobson and others 1997; Jacobson and others 2001; Jenkins and others 1984; Revuz and others 1990; Ricer 1989; Taylor and others 1993; Inconclusive evidence (statistically insignificant) Cree and others 1978 Conflicting evidence Lu Muzio and others 2001; Saxen and others 1997 Other variables were being compared e.g. use of adhesive / delivery vehicle Femiano and others 2003 Used an existing therapy as control (rather than placebo or no treatment) Pedersen and others 1990; Pedersen and others 1990 Did not have washout period to rule out lingering effects of 1st treatment Rattan and others 1994 Poor study design 1. Atik U, Cimen M, Eskandari G, Ikizoglu G, Kaya T and Tursen U. Oxidant/antioxidant status in patients with recurrent aphhthous stomoatitis. Clinical and Experimental Dermatology 2003; 28:647-650.2. Brice S. Clinical evaluation of the use of low-intensity ultrasound in the treatment of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1997; 83(1):14-20.3. Chadwick B, Addy M and Walker DM. Hexetidine mouthrinse in the management of minor aphthous ulceration and as an adjunct to oral hygiene. Br Dent J 1991; 171:83-7.4. De Cree J, Verhaegen H, De Cock W, and Verbruggen F. A randomized double-blind trial of levamisole in the therapy of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1978; 45 (3):378-84.5. Drinnan AJ and Fischman SL. Randomized, double-blind study of levamisole in recurrent aphthous stomatitis. J Oral Path 1978; 7(6):414-17.6. Femiano F, Gombos F, and Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol 2003; 42(5):394-7.7. Fridh G and Koch G. Effect of a mouth rinse containing amyloglucosidease and glucose oxidase on recurrent aphthous ulcers in children and adolescents. Swed Dent J 1999; 23:49-57.8. Garnick JJ, Singh B, and Winkley G. Effectiveness of a medicament containing silicon dioxide, aloe, and allantoin on aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86(5):550-56.9. Hodosh A, Hodosh M, and Hodosh M. Treatment of aphthous stomatitis with saturated potassium nitrate/dimethyl isosorbide. Quintessence International 2004; 35 (2):137-144.10. Jacobson JM, Greenspan JS, Spritzler J, Fox L, Fahey JL, Jackson JB, Chernoff M, Wohl DA, Pulvirenti JJ, Hooton TM, and Shikuma C. Thalidomide in low intermittent doses does not prevent recurrence of human immunodeficiency virus-associated aphthous ulcers. J Infect Dis 2001; 183(2):343-6.11. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail LA, Vasquez GJ, and Wohl DA. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997; 336(21):1487-93.12. Jenkins JS, Powell RJ, Allen BR, Littlewood SM, Maurice PD, and Smith NJ. Thalidomide in severe orogenital ulceration. Lancet 1984; 2(8417-18):1424-6.13. Lo Muzio L, della Valle A, Mignogna MD, Pannone G, Bucci P, Bucci E, and Sciubba J. The treatment of oral aphthous ulceration or erosive lichen planus with topical clobetasol propionate in three preparations: a clinical and pilot study on 54 patients. J Oral Pathol Med 2001; 30(10):611-7.14. Matthews RW, Scully CM, Levers BGH, and Hislop WS. Clinical evaluation of benzydamine, chlorhexidine, and placebo mouthwashes in the management of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1987; 63:189-91.15. Miles DA, Bricker SL, Razmus TF, and Potter RH. Triamcinolone acetonide versus chlorhexidine for treatment of recurrent stomatitis. Oral Surg Oral Med Oral Pathol 1993; 75:397-402.716. Olson JA and Silverman S. Double-blind study of levamisole therapy in recurrent aphthous stomatitis. J Oral Path 1978; 7(6):393-9.17. Pedersen A, Hougen HP, Klausen B, and Winther K. LongoVital in the prevention of recurrent aphthous ulceration. J Oral Pathol Med 1990; 19:371-37518. Pedersen A, Klausen B, Hougen HP, Ryder L, and Winther K. Immunomodulation by LongoVital in patients with recurrent aphthous ulceration. J Oral Pathol Med 1990; 19:376-380.19. Revuz J, Guillaume JC, Janier M, Hans P, Marchand C, Souteyrand P, Bonnetblanc JM, Claudy A, Dallac S, and Klene C. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Archives of dermatology 1990; 126(7):923-7.20. Saxen MA, Ambrosius WT, Rehemtula al-KF, Russell AL, and Eckert GJ. Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84(4):356-61.21. Taylor LJ, Walker DM, and Bagg J. A clinical trial of prostaglandin E2 in recurrent aphthous ulceration. Br Dent J 1993; 175:125-9.22. Rattan J, Schneider M, Arber N, Gorsky M, and Dayan D. Sucralfate suspension as a treatment of recurrent aphthous stomatitis. Journal of internal medicine 1994; 236:341-343 23. Ricer RE. Sucralfate vs. Placebo for the treatment of aphthous ulcers: A double-blinded prospective clinical trial. Family practice research journal 1989; 9(1):33-41