DOI: https://doi.org/10.62204/2336-498X-2025-2-13

CLINICAL ASSESSMENT OF THE LOCAL INHIBITION OF MATRIX METALLOPROTEINASES FOR MANAGING SYMPTOMS OF ORAL ULCERS

Andriy Samoilenko,
Doctor of Science in Medicine, Professor,
Dnipro State Medical University, Ukraine,
savdsma2017@gmail.com; ORCID: 0000-0003-1758-6442

Tetiana Strelchenia,
Ph.D., Assistant Professor,
Dnipro State Medical University, Ukraine,
t2012s@i.ua; ORCID: 0000-0002-6638-8859

Annotation. Oral ulcers are very common in dental practice, their treatment is quite challenging, and as yet, there is no definitive cure. Matrix Metalloproteinase is an interstitial collagenase which is thought to play an important role in tissue destruction events in recurrent oral ulceration. Tetracyclines have anti-collagenase and anti-inflammatory effects, explaining their therapeutic action in the treatment of recurrent oral ulcers.

Keywords: oral ulcers, matrix metalloproteinase, chronic recurrent aphthous stomatitis, topical tetracycline.

Introduction. Ulcers of the oral mucosa are common lesion that can severely impact patient quality of life by interfering with swallowing, drinking, eating and even speaking. The pain causes the patient to modify habits of hygiene and diet. Usually, oral ulcers include conditions such as local trauma, chronic recurrent aphthous stomatitis, viral and bacterial infections, allergic reactions, adverse drug reactions, or systemic disease (Fitzpatrick SG, Cohen DM, Clark AN., 2019; Schemel-Suárez M, López-López J, Chimenos-Küstner E., 2015). Chronic recurrent aphthous stomatitis is a common type of oral ulcer that characterized by recurrent, painful ulcers with a necrotic base and well defined limits surrounded by an erythematous halo on the oral mucosa. The prevalence range of the chronic recurrent aphthous stomatitis in the general population is 0.7–50% (Parra-Moreno FJ et al., 2023). It is more common in patients between 10-40 years of age, and predominantly affects women and individuals of higher socioeconomic levels. Chronic recurrent aphthous stomatitis have uncertain etiology and causes are not fully elucidated. Although the formation of the aphthous lesions follows a common pattern, triggers vary between individuals and may include local factors such as minor trauma, altered microbiota, parafunctional habits, and systemic factors such as genetic predisposition, nutritional   deficiencies (e.g., ferritin, zinc, and selenium), chronic gastrointestinal disorders, allergies, hematologic conditions, and systemic medications (e.g., captopril, phenobarbital, diclofenac, and piroxicam) have been implicated in previous studies (Giannetti L, Murri Dello Diago A, Lo Muzio L., 2018).

Clinical presentation includes of minor, major, and herpetiform ulcers (Manfredini M. et al., 2021) Minor ulcers are the most common, representing over 80% of cases. They are characterized by small painful ulcers (5–10 mm) with a well-defined border that appears on non-keratinized mucosae such as the buccal mucosa, labial mucosa, tongue, soft palate, and pharynx. Major ulcers that account for about 10% of all cases are larger (diameter exceeds 10 mm) and deep, can last for 6 weeks or longer, and are affecting both mucosa and keratinized tissues, and frequently heal with scaring. Herpetiform ulcers are mostly present as multiple small clusters of pinpoint lesions that form large irregular ulcers, and similar to minor ulcers, heal within 14 days without scaring.

No specific curative medicine is available due to the unknown etiology of recurrent ulceration (Parra-Moreno FJ et al., 2023). The most frequently employed treatments for oral ulcers are antimicrobial mouth-washes, topical corticosteroids, local analgesics, astringents, and laser therapy have been showed to be partially effective in alleviating patients symptoms and disease length (Manfredini M et al., 2021; Liu H et al., 2022). The management of oral ulcers poses a complicated problem for both clinicians and patients, and seeks to reduce inflammation of the aphthae, afford pain relief, to promote ulcer healing as well as the reduction of the frequency of recurrences and an increase in disease-free period.

Applying topical tetracyclines as efficient drug to the ulcer lesions had captured much attention (Mashrah MA. et al., 2023). One of the important positive properties of these agents in addition to the known antibiotic action is the inhibitory effect on matrix metalloproteinases (collagenases) that form part of the inflammatory response and contribute to tissue destruction and ulcer formation. Moreover, tetracyclines increase the adhesion of fibroblasts which contributes to the regeneration of damaged tissues, and this property is other possible mechanism suggesting its potential curative benefits. The anti-inflammatory properties of tetracyclines and its efficacy in chronic recurrent ulceration have been shown in several previously conducted studies. It has found a significant improvement in the signs and symptoms associated with oral ulcerative lesions. Chugh A et al., 2022 reported significant reduction or even suppression the pain and shortening the aphthae healing time using tetracycline mouthwashes four times a day. As pointed out by other authors (Al-Maweri SA et al., 2020; Mashrah MA et al., 2023), it is advisable to apply the medication directly onto the lesions, keeping it in direct contact for as long as possible.

Clinical trials on new agents with tetracycline as an active ingredient are still ongoing. Therefore, using a similar local drug to assess efficacy could be relevant.

The purpose of the article is to assess a potential benefit of topical tetracycline (TetraNext) in the treatment of oral ulcers.

The research methodology. Based on the inclusion and exclusion criteria, 57 patients (33 women and 24 men) who visited the department of therapeutic dentistry and FPE dentistry of the Dnipro State Medical University (Ukraine) with complaints of oral ulcers participated in the study. All patients agreed to participate in the study and therefore they did sign the consent form.

To decrease the number of variables affecting the recurrent ulcers pathophysiology and pharmacology, we narrowed the patients’ age range between 18 and 35 years. The average subjects age was 27,3±13,03 years. The patients with minor recurrent ulcer singular lesions in an easily accessible area of the mouth without any other medical complications who had noticed oral lesions during the last two days were included in this study. Patients with systemic diseases, iron, vitamin B₁₂ and/or folic acid deficiency, pregnant mothers and smokers were excluded from the study.

The patients were allocated into two groups: test group (n=28) and control group (n=29). The groups were not significantly different in the female to male ratios and their mean age, ulcer histories.

The participants were instructed to rinse their mouth with 0,05% chlorhexidine and apply TetraNext (test group) or Aecol (control group) on the lesions four-times a day (after meals and before bed time) for as long as the lesions persist. Participants it was recommended not to eat or drink anything for 30 minutes after application of the agents in all groups. All patients were strictly warned not to use any other products for the treatment of ulcers while participating in this study. At the end of therapy, all patients were also asked to report any adverse effects of the agents.

Assessment of the effectiveness of topical management of chronic oral ulcers was made according to three criteria: pain intensity, lesions’ diameters and inflammation zone on the third and seventh days of the therapy.

The quantify pain intensity was recorded using a paper visual analog scale /VAS/ (ranging from 0 /no pain/ to 10 /unbearable pain/). Scores from 0 to 10 were noted on the vertical line, and participants had to circle the level of their pain. Using a calibrated periodontal probe, the ulcer size and their inflammatory zone were calculated.

Patients with lesion diameter less than 1mm and pain score of 1 were considered healed.

TetraNext (Balkanpharma-Razgrad AD, Bulgaria) which recently appeared on the Ukrainian pharmaceutical market is a topical agent that contains tetracycline hydrochloride as an active ingredient and mineral oil gel base as an inactive substances. TetraNext is supplied in the form of an ophthalmic ointment at a concentration of 0.1%. Aecol is a solution containing an oil solution of retinol acetate, alpha-tocopherol acetate and vikasol. Both agents form a lipid film on the ulcer surface that protects against mechanical injury and can help reduce oral moisture loss and inflammation.

All of the data was analyzed using statistical tests (unpaired students t-test) and p value of less than 0,05 was considered to be statistically significant.

Two out of fifty-seven participants enrolled in the study stopped their treatment course for no specific reason therefore 27 subjects in control group and 28 subjects in test group completed the study (total 55).

Results of research. Аt study entry the high lesion pain level (ranging from 8 to 10) which patients indicated was found in 19 patients; almost half of all participants (41.8%) reported a mean pain level (ranging from 5 to 7); smaller percentages (23.6%) are related to low VAS scores (ranging from 0 to 4). The total mean VAS score in our study was 5.82 associated with the highest perception of pain аs a symptom of chronic recurrent aphthous stomatitis.

Pain relief in the days following treatment was recorded in both groups. However, significant differences were showed in pain evaluation when comparing the results of local use of TetraNext and standard local therapy of oral ulcers. Overall, the mean pain scores were all higher in patient controls than mean pain scores in patients treated TetraNext for the same period suggesting that the tetracycline is able to pain relief.

On the third day high pain levels were more often found in control group than in patient TetraNext-treated (18.5% vs 7.14% respectively). Symptomatology improved by at least 50% (good response) in 11 (39.3%) patients of the test group and only 8 (29.6%) patients in the control group for a given period of assessment (P <0.001). Seven (25%) patients in the test group did not complain of pain while in the control group only 4 (14.8%) reported complete cessation of pain (P <0.001). The mean VAS scores decreased by 46.9% in the test group and by 32.6% in the control group when compared with the baseline data.

The pain scores in the test group were found statistically lower on the seventh day as well. Efficacy of TetraNext in treatment protocol of recurrent ulceration, regarding pain score, was higher than the control group which is confirmed by a 5.3-fold decrease in mean VAS scores relative to the baseline data. When compared with test group the mean pain dimensions in patients controls decreased by 3.6 times. In contrast to 66.7% of the patients in the control group, 75% of the patients treated TetraNext in the present study noted the absence of pain on the seventh day of treatment.

Regarding the lesions’ diameters at study entry, their mean size in the control group was 2.73 ± 0.66 mm, while 2.69 ± 0.71 mm in the TetraNext treatment group. The mean values of the inflammation zone (erythema diameter) in the test group were 4.19 ± 1.01, in the controls – 4.11 ± 1.05 (p>0.05).

Although the baseline ulcer size was similar in groups at the beginning of the study (p> 0,05), significant differences were detected after 3 days.

The prevalence of healing episodes confirms the therapeutic benefits of TetraNext. On the third day 10.71% patients with complete epithelialization of the oral mucosa and 21.4% patients with reduction more than half lesion diameter in the test group was observed. These data were 3.7% and 11.1% in the control group, respectively. Furthermore, more than half (55.6%) of patients in the control group did not change of lesion diameter, on third day of treatment. While only 10 (35.71%) patient in the test group had a baseline ulcer size.

The lesions’ diameters in the test group became significantly smaller than in the control group after third day – 2.07mm±0.44 and 2.19mm±0.63mm respectively.

Significant group differences were also found at the later visit.

The advantage of the wound-healing properties of TetraNext over standard therapy of recurrent ulcers on the seventh day of observation was more clearly manifested. The mean ulcer size of the test group was almost two times higher than in patients of the control (0.69±0.62 vs 1.34±0.58 respectively). Sixteen of 28 patients treated with TetraNext application had the complete regeneration of damaged oral tissues, while 11 of 27 patients in control had a similar response (P<0.001).

The reduction in erythema diameter of the test group was found much greater at the third day and the seventh day when compared with control group (2.96±0.71 and 1.16±1.05 vs 3.53±0.69 and 2.18±0.88 respectively). Our interpretation of these results is that the clinical beneficial effects of TetraNext could be attributed to the ability to decrease inflammation by inhibition of the matrix metalloproteinases.

The pain and lesion in both groups on the tenth day were considered healed based on the patients’ self-reports.

Topical tetracycline (TetraNext) is safe when used in treatment of recurrent oral ulceration. No side-effects were found in both groups.

Conclusions. Oral ulceration is a relatively common oral mucosal condition. Recurrent oral ulcers have an important effect on the patients’ excellence of life, causing much pain and difficulty with mastication and speech.

Management of oral ulcers is challenging. Symptomatic treatment ranges from mouthwash rinses to systemic agents. For recurrent aphthous ulcers, topical medications are preferred due to their minimum side effects. Topical tetracyclines are very important in the treatment of ulcers due to the inhibition of matrix metalloproteinases, which are associated with tissue destruction.

The present study revealed that topical tetracycline to be effective in accelerating the healing of recurrent oral ulcers and in lessening the pain, erythema and size of the oral lesions.

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