INTRODUCTION:

[1] The term “aphthous” is derived from a Greek word “aphtha” which means ulceration. Recurrent aphthous stomatitis (RAS) is one of the most common painful oral mucosal conditions seen among patients. These present as recurrent, multiple, small, round, or ovoid ulcers, with circumscribed margins, having yellow or gray floors and are surrounded by erythematous haloes, present first in childhood or adolescence.[2]

Recurrent aphthous ulceration has three different variants—minor aphthous ulcers, major aphthous ulcers and herpetiform ulcers, according to the classification described by Stanley in 1972 [3]. In the pre-ulcerative stage, a mononuclear cell infiltrate in the epithelium is followed by a localised papular swelling as a result of keratinocytes vacuoles action representing vasculitis [4]. The lesion then ulcerates and is covered by a fibrous membrane, which is infiltrated mainly by neutrophils, lymphocytes, and plasma cells. The immunopathogenesis probably involves cell mediated responses ,involving T cells and tumor necrosis factor alpha (TNFalpha) production by these and other infiltrating leukocytes( mast cells and macrophages) [5]. Effects on endothelial cell adhesion and neutrophil chemo taxis by TNF-alpha induces inflammation[6]. The etiology of RAS lesions is unknown, but several local, systemic, immunologic, genetic, allergic, nutritional, and microbial factors have been proposed ascausative agents [4]. The onset of RAS seems to peak between the ages of 10 and 19 years and becoming less frequent with advancing age [7].

DIAGNOSIS

Diagnosis is mostly based on the clinical appearance and the medical history [8]. The most important diagnostic feature is a history of recurrent, self-healing ulcers at fairly regular intervals [9]. Recurrent oral ulceration has relatively few causes, most commonly aphthous stomatitis, but rarely Bechtel’s disease, erythema multiforme, ulceration associated with gastrointestinal disease[9,10]. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history[11].Special investigations may be indicated to rule out other causes of oral ulceration. These include blood tests to exclude anaemia, deficiencies of iron, folate or vitamin B12 or celiac disease[12]. However, the nutritional deficiencies may be latent and the peripheral blood picture may appear relatively normal[7]. Patch testing may be indicated if allergies are suspected .Several drugs can cause oral ulceration e.g.; nicorandil [8].

TREATMENT

Existence of different approaches to the Management of apthous ulcers comes down to treatment of the patient in the dental clinic which falls under 3 categories. They are;

1. Initial clinical evaluation and non-pharmacological treatment

A first requirement is a full and detailed clinical history [13, 14]. In certain cases complementary measures are recommended such as a complete blood test including red cell count, folic acid, ferritin and vitamin B12, with the purpose of discarding possible underlying systemic causes (vitamin deficiencies, gastrointestinal disease, Behçet’s syndrome, immune deficiencies) – particularly in the case of adults who suffer sudden outbreaks of RAS, in patients with major aphthae, or when there are also lesions in other parts of the body [13,14,15] . Due to the relationship between RAS and vitamin deficiencies, some authors such as Volkovet al [16] have reported that treatment with vitamin B12, apart from being simple, inexpensive and of low risk, proves effective in application to RAS, even independently of the serum vitamin B12 levels of the patient. Treatment with 2 g of vitamin C a day during three months has also been shown to be effective [17]. However, some studies reveal that daily multivitamin supplements are unable to reduce either the number or the duration of RAS outbreaks, and therefore consider that physicians should not recommend such supplements on a routine basis as preventive treatment [18]. Mainly, the treatment prescribed should be conditioned to the severity of the disease (pain), the medical history of the patient, the frequency of the outbreaks, and patient tolerance of the medication [13,19].

2. Local pharmacological treatment

-topical therapy

Treatment should always begin with topical medication The first line treatment options comprise

1. Antiseptics and antiinflammatory drugs/analgesics :

As 0.2% chlorhexidine in rinses or gel, three times a day (without swallowing), for as long as the lesions persist. Triclosan can also be used in gel or rinse format three times a day (without swallowing), for as long as the lesions persist, and affords antiinflammatory, antiseptic and analgesic effects. In turn, topical 3% diclofenac with 2.5% hyaluronic acid can be applied to lessen the pain [20]. There have also been reports of the use of oral rinses with benzidamine hydrochloride, which offers temporary pain relief [19,20].Amlexanox is a widely studied drug that offers short-term efficacy, particularly when used in the prodromic (early symptoms) phase.It is a topical agent with established antiinflammatory and antiallergic properties [19].It is usually supplied in the form of an ointment at a concentration of 5%, and is applied 2-4 times a day. The drug has been shown to be effective in accelerating the healing of aphthae and in lessening the pain, erythema and size of the lesions [21].

2. Topical antibiotics:

such as tetracyclines and their derivatives (doxycycline and minocycline), in gel or rinse format, have also been found to lessen the pain and outbreaks of RAS. These drugs act through the local inhibition of collagenases and metalloproteinases (MPs) that form part of the inflammatory response and contribute to tissue destruction and ulcer formation, and moreover exert immune modulating effects [19]. Of the commercially available tetracyclines, doxycycline has shown the best inhibition of MPs [22].

3. Immmune modulators:

In immune-mediated oral mucosal diseases the most widely used drugs are the topical corticosteroids. The aim of such treatment is to eliminate the symptoms, thereby allowing the patient to eat, speak and perform normal oral hygiene, since topical corticosteroids reduce or even suppress the pain and shorten the aphthae healing time [23]. In patients with RAS, the indicated drugs are triamcinolone acetonide, fluocinoloneacetonide or clobetasol propionate, according to the severity of the lesions. Triamcinolone acetonide is indicated in patients with small and mild erosive lesions [20,23] ,Another evaluated topical corticosteroid is dexamethasone. Liu et al. [24] investigated the efficacy and safety of dexamethasone pomade in treating RAS.topicalanesthetics such as 2% lidocaine (as a spray or gel); adhesive toothpaste containing polydocanol; or benzocaine tablets [13,20].

Systemic therapy

Studies have been made of systemic antibiotics such as potassium penicillin G in 50 mg tablets administered four times a day during four days, which help reduce the size of the ulcers and lessen the pain [25].The most effective treatments include corticosteroids and immunosuppressors. Pentoxifylline, colchicine, dapsone and thalidomide have also been used, but require caution because of possible adverse effects. These treatments are essentially palliative, since none of them have been able to secure permanent disease remission [26].Oral prednisone has been used at a starting dose of 25 mg/day, followed by stepwise dose reduction, during two months, with disappearance of the pain and reepithelization of the lesions in the first month of therapy [26]. The drug can produce long-term adverse effects; as a result, its efficacy has been compared with that of other drugs . As regards adverse effects, montelukast was found to be safer, and therefore should be taken into account as an option when systemic corticosteroids are contraindicated. [27]Clofazimine is an antimicrobial used for treatment[28].Scully et al. [20] recommend the use of pentoxifylline, and inhibitor of tumor necrosis factor-alpha (TNF-α), and of neutrophil function and chemotaxis. Immune modulators may be useful as second line treatment in different oral diseases such as oral lichen planus, and particularly in recurrent aphthous stomatitis [29]. In this context, thalidomide, an immune modulator widely used in RAS, is recommended at a dose of 50-100 mg/day [20]. Thalidomide is known to produce many adverse effects, including teratogenicity, polyneuropathy, drowsiness, constipation, increased appetite, headache, nausea and gastric pain [20,30]. Another immune modulator is levamisole, which restores normal phagocytic activity among macrophages and neutrophils, and modulates T cell mediated immunity. The drug shortens the duration of the aphthae outbreaks, as well as the number, size and frequency of the lesions [12,31].

CONCLUSION:

Also other systemic treatments have been discovered, including homeopathic medicines containing borax, mercuriussolubilis, natrummuriaticum, phosphorus, sulfuric acid, nitric acid, arsenicum album, nux vomica and lycopodium. However, there is still not enough evidence to either support or refute the use of homeopathic medicines as treatment for recurrent apthous stomatitis [32].While RAS remains a common oral mucosal disorder inmost communities of the world, and is currently recognized asan immunologically mediated, inflammatory oral condition rather than an infectious disease.

REFERENCES:

1. http://upload.wikimedia.org/wikipedia/commons/2/2d/aptha2.jpg

2. Jurge S, Kuffer R, Scully C, Porter SR. Recurrent aphthous stomatitis. Oral Dis. 2006;12:1–21.

3. Akintoye SO, Greenberg MS. Recurrent aphthous stoma-titis.DentClin North Am2005;49: 31–47

4. Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg. 2008;46:198-206.

5. Taylor LJ, Bagg J, Walker DM, et al. Increased production of tumour necrosis factor by peripheral blood leukocytes in patients with recurrent oral aphthous ulceration. J Oral Pathol Med. 1992;21:21-25.

6. Natah SS, Hayrinen-Immonen R, Hietanen J, et al. Increased density of lymphocytes bearing gamma/delta T-cell receptors in recurrent aphthous ulceration (RAU). Int J Oral Maxillofac Surg. 2000;29:375-380.

7. Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrentaphthous stomatitis. Quintessence Int2000;31;95-112.

8. Scully C (2013). Oral and maxillofacial medicine: the basis of diagnosis and treatment (3rd ed.). Edinburgh: Churchill Livingstone. pp. 226–234.

9. Cawson RA, Odell EW, Porter S (2008). Cawson's essentials of oral pathology and oral medicine (8th ed.). Edinburgh: Churchill Livingstone. pp. 220–224.

10. Odell W (2010). Clinical problem solving in dentistry (3rd ed.). Edinburgh: Churchill Livingstone. pp. 87–90.

11. Scully C, Porter S (March 31, 2008). "Oral mucosal disease: Recurrent aphthous stomatitis". British Journal of Oral and Maxillofacial Surgery 46 (3): 198–206. doi:10.1016/j. bjoms.2007.07.201

12. Millet D, Welbury R (2004). Clinical problem solving in orthodontics and paediatric dentistry. Edinburgh: Churchill Livingstone. pp. 143–144.

13. Chavan M, Jain H, Diwan N, Khedkar S, Shete A, Durkar S. Recurrent aphthousstomatitis:a review. J Oral Pathol Med. 2012;41:577–83.

14. Preeti L, Magesh KT, Rajkumar K, Karthik R. Recurrent aphthous stomatitis. J Oral MaxillofacPathol. 2011;15:252–6.

15. Liang MW, Neoh CY. Oral aphthosis: management gaps and recent advances. Ann Acad Med Singapore. 2012;41:463–70.

16. Volkov I, Rudoy I, Freud T, Sardal G, Naimer S, Peleg R. Effectiveness of vitamin B12 in treating recurrent aphthousstomatitis: a randomized, double-blind, placebo-controlled trial. J Am Board Fam Med. 2009;22:9–16.

17. Yasui K, Kurata T, Yashiro M, Tsuge M, Ohtsuki S, Morishima T. The effect of ascorbate on minor recurrent aphthous stomatitis. ActaPaediatr. 2010;99:442–5.

18. Lalla RV, Choquette LE, Feinn RS, Zawistowski H, Latortue MC, Kelly ET. Multivitamin therapy for recurrent aphthousstomatitis: a randomized, double-masked, placebo-controlled trial. J Am Dent Assoc. 2012;143:370–6.

19. Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC, Latortue MC, Carrozzo M. Urban legends: recurrentaphthous stomatitis. Oral Dis. 2011;17:755–70.

20. Scully C, Porter S. Oral mucosal disease:recurrentaphthous stomatitis. Br J Oral Maxillofac Surg. 2008;46:198–206.

21. Meng W, Dong Y, Liu J, Wang Z, Zhong X, Chen R. A clinical evaluation of amlexanox oral adhesive pellicles in the treatment of recurrent aphthous stomatitis and comparison with amlexanox oral tablets:a randomized, placebo controlled, blinded, multicenter clinical trial. Trials. 2009;10:30.

22. Skulason S, Holbrook WP, Kristmundsdottir T. Clinical assessment of the effect of a matrix metalloproteinase inhibitor on aphthous ulcers. ActaOdontol Scand. 2009;67:25–9.

23. Quijano D, Rodríguez M. [Topical corticosteroids in recurrent aphthous stomatitis. Systematic review] Acta Otorrinolaringol Esp. 2008;59:298–307.

24. Liu C, Zhou Z, Liu G, Wang Q, Chen J, Wang L. Efficacy and safety of dexamethasone ointment on recurrent aphthous ulceration. Am J Med. 2012;125:292–301.

25. Zhou Y, Chen Q, Meng W, Jiang L, Wang Z, Liu J. Evaluation of penicillin G potassium troches in the treatment of minor recurrent aphthous ulceration in a Chinese cohort:a randomized, double-blinded, placebo and no-treatment-controlled, multicenter clinical trial. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2010;109:561–6.

26. Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers) Cochrane Database Syst Rev. 2012;9:CD005411.

27. Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N. Pilot study on recurrent aphthous stomatitis (RAS):a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2010;109:402–7.

28. de Abreu MA, Hirata CH, Pimentel DR, Weckx LL. Treatment of recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2009;108:714–21.

29. Elad S, Epstein JB, von Bültzingslöwen I, Drucker S, Tzach R, Yarom N. Topical immunomodulators for management of oral mucosal conditions, a systematic review;PartII:miscellaneous agents. Expert OpinEmerg Drugs. 2011;16:183–202.

30. Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Use of thalidomide for severe recurrent aphthousstomatitis: amulticenter cohort analysis. Medicine (Baltimore) 2010; 89:176–82.

31. Weckx LL, Hirata CH, Abreu MA, Fillizolla VC, Silva OM. [Levamisole does not prevent lesions of recurrent aphthousstomatitis:a double-blind placebo-controlled clinical trial] Rev Assoc Med Bras. 2009;55:132–8.

32. Mousavi F, Mojaver YN, Asadzadeh M, Mirzazadeh M. Homeopathic treatment of minor aphthousulcer:a randomized, placebo-controlled clinical trial. Homeopathy. 2009;98:137–41.

Received on 19.07.2014 Modified on 22.08.2014

Research J. Pharm. and Tech. 7(10): Oct. 2014 Page 1193-1195