Efficacy of hyaluronic acid for recurrent aphthous stomatitis: a systematic review of clinical trials

Clin Oral Investig. 2021 Dec;25(12):6561-6570. doi: 10.1007/s00784-021-04180-4. Epub 2021 Sep 20.


Objectives: Recurrent aphthous stomatitis (RAS) is a very common oral mucosal disease, and its management is quite challenging with no definitive cure being available so far. Many studies have tried hyaluronic acid (HA) for alleviating signs and symptoms of RAS. The present systematic review sought to assess the available evidence regarding the efficacy of HA in management of RAS.

Methods: Two reviewers independently conducted extensive search in four online databases (PubMed, Scopus, Web of Science, and Google Scholar) and the gray literature, with no restriction to date or language of the publication. All clinical trials that assessed the efficacy of HA in reducing signs and symptoms of RAS were included. Risk of bias was assessed by two reviewers independently, using the Cochrane assessment tool. Due to substantial heterogeneity, no meta-analysis was feasible.

Results: Out of the 75 identified articles, nine clinical trials involving 538 RAS patients (259 in HA group) were included. The risk of bias was high in five studies, low in one study, and unclear in three studies. The comparative groups varied greatly across the included studies: triamcinolone (in three studies), chlorhexidine mouthwash, lidocaine, placebo, iodine glycerin, diclofenac, and laser therapy. Overall, the results revealed a good efficacy of HA in alleviating pain and shortening the healing time of RAS, without any reported side effects. Compared to triamcinolone, HA showed superior results in one study, and comparable results in two studies.

Conclusions: The available evidence suggests that HA is a promising treatment option for RAS. However, given the huge heterogeneity of the included studies and high risk of bias in some of these studies, the evidence is inconclusive. Further well-designed clinical trials with standardized methodologies and adequate sample sizes are warranted to discern the efficacy of HA for RAS.

Clinical relevance: Hyaluronic acid might be a viable alternative therapeutic option for patients with RAS.

Keywords: Aphthous stomatitis; Efficacy; Hyaluronic acid; Management.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Humans
  • Hyaluronic Acid
  • Low-Level Light Therapy*
  • Mouth Diseases*
  • Pain
  • Stomatitis, Aphthous* / drug therapy


  • Hyaluronic Acid