Recurrent aphthous stomatitis is a common disorder of the oral cavity, affecting mainly young people. It is characterized by small ulcers which can be very painful and generally heal spontaneously within 7–14 days. There is currently no therapy that can provide rapid healing.
This study evaluated the efficacy and rapidity of response of a lozenge containing
Recurrent aphthous stomatitis (RAS) is characterized by spontaneously self-limiting ulcerations of the mucosa of the oral cavity. The lesions can be single or multiple and generally affect the nonkeratinized mucosa of the cheeks, the soft palate, the fauces, the mouth floor, the tongue, and the gums.
This pathology can be observed in 20–30% of the population and most commonly affects the higher social classes [
Recurrent aphthous stomatitis can be divided into three categories according to the characteristics of the ulcer: major, minor, and herpetiform. The major form is characterized by painful ulcers (>10 mm) which erode the mucosa creating deep ulcers located on the palate, tonsils, pharynx, or tongue, which generally heal—often forming a scar—within 2 weeks, but can sometimes take months. The minor form is the most common and represents about 80% of all cases of recurrent aphthous stomatitis. Clinically, it presents painful, small (5–10 mm), well-defined ulcers, which are round or oval in shape; they usually affect the buccal or labial mucosa and heal in about 7–10 days. The herpetiform type is named after its likeness to
A detailed clinical history should be taken for each case of recurrent aphthous stomatitis in order to exclude other diseases that can present aphthous-like lesions such as Behçet’s syndrome, Crohn’s disease, human immunodeficiency virus (HIV) infection, and neutropenia [
The etiology of recurrent aphthous stomatitis is still unknown, although many predisposing factors have been described: trauma, stress, changes in the immune system, sensitivity to certain types of food, or ingested substances such as preservative agents or cinnamaldehyde (a substance contained in some toothpastes), iron, zinc, and vitamin deficiency [
The treatment of recurrent aphthous stomatitis remains unsatisfactory and frustrating for both patients and doctors. Patients are asked to brush delicately and avoid eating any hard, sharp, or irritating foods. Topical steroids at best reduce the pain but not the rate of recurrence; moreover they can cause systemic effects. Topical tetracycline and chlorhexidine may reduce the severity of the inflammation but not the frequency. In severe cases, systemic steroids, thalidomide, colchicine, pentoxifylline, azathioprine, alpha 2 interferon, and cyclosporine are considered as possible options for the patients, but again the side effects can be significant.
Previous studies have shown
The
The primary aim of this study was to evaluate the efficacy and time to remission with a lozenge containing at least 1 billion
Secondary endpoints included assessment of the variations of prostaglandin E2 (PEG2), Interferon-
The study was conducted in a double-blind, placebo-controlled fashion on 30 patients, 15 (7 male and 8 female) aged between 8 and 36, treated with lozenges containing
1 lozenge containing
Each lozenge was composed of the following: lyophilized bacteria of
Placebo consisted of a lozenge containing excipients only, supplied in the same packaging and administered in the same way and at the same dosage as the active product.
The criteria for inclusion in the study included a history of recurrent minor aphthous stomatitis (at least 3 episodes in a year), characterized by painful ulcers of 1–10 mm in diameter that had arisen no more than 48 hours prior to enrolment and which generally had an expected clinical resolution of 5 or more days.
Exclusion criteria for this study were patients with diabetes mellitus, alcohol and/or drug abuse, or patients who had undergone dental interventions or taken antibiotic therapy in the two weeks prior to enrolment. Also excluded from the study were patients who had taken anti-inflammatory steroid and nonsteroid therapy within 30 days prior to enrolment.
All patients were informed about the study and the characteristics of the product and signed informed consent at enrolment.
All patients were subjected to evaluation of clinical and laboratory parameters at the start of therapy (T0), and at the end of treatment (T1).
The following clinical signs and symptoms were taken into account: spontaneous pain, local burning, and perilesional erythema. The intensity of the signs and symptoms was expressed as 0: absent, 1: mild, 2: moderate, 3: severe.
Moreover the total sum of the diameters of the greater individual ulcers, expressed in millimeters, was calculated at enrolment and at the end of treatment.
Particular attention was given to the assessment of pain: patients were asked to score the intensity of spontaneous pain based on the Numerical Rating System scale from 1 to 10, considering a rating from 1 to 4 as mild pain (score = 1), >4 to 7 as moderate (score = 2) and >7 to 10 as severe pain (score = 3).
A questionnaire about observed daily changes in pain was handed out, in which patients were asked to fill in, sign and return at the end of treatment.
Salivary samples were collected in all patients to assess PGE2, IFN
IFN
In aqueous solutions, NO reacts rapidly with O2 and accumulates in the culture medium as nitrite and nitrate ions. Twenty microliters of saliva samples or supernatants from macrophage cultures were used for nitrite measurement by colorimetric assay based on the Griess reaction. Briefly, 5 ml of HEPES (50 mM, ph 7.4), 5
Differences in the analyzed parameters between active and control groups were tested using the Student’s
All patients enrolled in the study completed the trial.
From a clinical point of view, 14 of 15 patients (93.3%) treated with
Clinical evaluation.
The sum of diameters of the greater individual ulcers at enrolment was 112 mm in the
Sum of greater diameters.
The pattern and the intensity of individual clinical signs and symptoms under review was as indicated in Table
Summary of clinical parameters before and after administration of
Placebo ( | Intergroup comparison | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Severe ( | Moderate ( | Mild ( | Absent ( | Total Value | Severe ( | Moderate ( | Mild ( | Absent ( | Total value | |||
Burning | before | 7 | 5 | 3 | 0 | 34 | 8 | 4 | 3 | 0 | 35 | |
after | 0 | 0 | 1 | 14 | 1 | 2 | 4 | 2 | 7 | 16 | ||
Spontaneous pain | before | 6 | 6 | 3 | 0 | 33 | 7 | 5 | 3 | 0 | 34 | |
after | 0 | 0 | 1 | 0 | 1 | 3 | 4 | 1 | 7 | 18 | ||
Caused pain | before | 9 | 6 | 0 | 0 | 39 | 10 | 5 | 0 | 0 | 40 | |
after | 0 | 0 | 1 | 14 | 1 | 5 | 2 | 1 | 7 | 20 | ||
Perilesional erythema | before | 6 | 7 | 2 | 0 | 34 | 7 | 5 | 3 | 0 | 34 | |
after | 0 | 0 | 1 | 0 | 1 | 3 | 4 | 1 | 7 | 18 |
Value assignment: 0: absent, 1: mild, 2: moderate, and 3: severe.
At enrolment burning was severe in 7 patients (intensity 21), moderate in 5 (intensity 10), and mild in 3 (intensity 3), with a total value of intensity equal to 34; at the end of therapy local burning persisted mildly only in 1 patient (intensity 1) with total value of intensity equal to 1.
At enrolment spontaneous pain was severe in 6 patients (intensity 18), moderate in 6 (intensity 12), and mild in 3 (intensity 3) with a total value of intensity equal to 33; after treatment it persisted as mild only in 1 patient (intensity 1) with a total value of intensity equal to 1 (Figure
Intensity of spontaneous pain.
At enrolment this was severe in 6 patients (intensity 18), moderate in 7 (intensity 14), and mild in 2 (intensity 2), with a total value of intensity equal to 34; at the end of therapy perilesional erythema persisted as mild only in 1 patient (intensity 1) with a total value of intensity equal to 1.
No side effects were observed and the tolerability of the therapy was judged as excellent by all patients.
At enrolment burning was severe in 8 patients (intensity 24), moderate in 4 (intensity 8), and mild in 3 (intensity 3), with a total value of intensity equal to 35; at the end of therapy local burning persisted as severe in 2 patients (intensity 6), moderate in 4 (intensity 8), and mild in 2 (intensity 2), with a total value of intensity equal to 16.
At enrolment pain was severe in 7 patients (intensity 21), moderate in 5 (intensity 10), and mild in 3 (intensity 3), with a total value of intensity equal to 34; after treatment spontaneous pain persisted as severe in 3 patients (intensity 9), moderate in 4 (intensity 8), and mild in 1 (intensity 1), with a total value of intensity equal to 18 (Figure
at enrolment this was severe in 7 patients (intensity 21), moderate in 5 (intensity 10) and mild in 3 (intensity 3), with a total value of intensity equal to 34; after therapy it persisted as severe in 3 patients (intensity 9), moderate in 4 (intensity 8) and mild in 1 (intensity 1), with a total value of intensity equal to 18.
No side effects were observed and the tolerability of therapy was judged as excellent by all patients.
The data provided by patients about the development of pain over time revealed a complete regression of pain in 14 of 15 patients treated with
At the end of therapy, there was a marked reduction in levels of PGE2, IFN
E Summary of laboratory parameters before and after administration of
Placebo | Intergroup comparison | |||
---|---|---|---|---|
Nitrite/Nitrate ( | (T0) | 42.38 ± 4,58 | 39.76 ± 5.08 | |
(T1) | 7.5 ± 1.5 | 27.5 ± 3.5 | ||
PGE2 (ng ml−1) | (T0) | 1.89 ± 0.2 | 1.77 ± 0.2 | |
(T1) | 0.40 ± 0.05 | 1.02 ± 0.3 | ||
IFN | (T0) | 32.25 ± 4.2 | 30.85 ± 4.2 | |
(T1) | 9.57 ± 1.7 | 21.07 ± 2.9 |
T0: before treatment; T1: after treatment.
In the normal microflora of the mouth, it is possible to isolate several thousand microbial species. These microorganisms create a dynamic equilibrium with the host immune system, allowing for proper defence mechanisms against pathogens. Some of these bacteria have a rich array of enzymes which enables them, through metabolic activities, to modify their surrounding environment.
Some lactic acid bacteria, and in particular the
The main symptom of which patients complain is intense pain; this is inevitably associated with considerable difficulty, and sometimes outright inability, in swallowing both solid and liquid foods. Even speech may be impaired, especially during the period of greater intensity of the stomatitis, because the pain increases. It is evident that pain is the main component of the considerable discomfort these patients suffer from. Such discomfort may also create significant social problems for the patient from both professional and personal standpoints. For this reason, our study focused primarily on the rapidity of response and reduction of pain. The results obtained from the study show that there is a rapid disappearance of pain after just 2-3 days of treatment. Only one patient who took the lozenge containing
The improvement in pain levels and especially the speed with which this improvement occurred is certainly the most interesting aspect that has emerged from this study and is related to the reduced production of Nitric Oxide (NO), one of the most powerful mediators of inflammation, which is able to modulate the production of inflammatory cytokines such as PGE2, IFN
Our findings clearly showed that all these inflammatory-associated markers were drastically reduced in recurrent aphthous stomatitis patients after treatment with
The reduced production of Nitric Oxide (NO) depends on arginine deiminase, an enzyme in which
There have been many attempts over the years to find an effective treatment for recurrent aphthous stomatitis.
Since the etiology of recurrent aphthous stomatitis remains unknown, its treatment consists of therapeutic measures that suppress the symptoms rather than bringing about a definitive cure. Choice of treatment depends on the severity of the disease, including the frequency of ulcer recurrence, the number of ulcers present, their location and duration, and the level of associated orofacial pain. Patients with mild-to-moderate symptoms and infrequent ulcers may only require palliative therapy for pain-like anesthetics, tissue, caustic, and cortisone adhesives. The use of immunosuppressive and anti-inflammatory drugs has demonstrated varying degrees of success in severe cases of recurrent aphthous stomatitis. Drugs commonly used include corticosteroids, dapsone, colchicine, thalidomide, pentoxifylline, low-dose interferon-
Because of their anti-inflammatory action, steroids are most often used in the treatment of recurrent aphthous stomatitis but their long-term administration can cause adverse reactions such as atrophy of the oral mucosa and minor resistance to infections. One must always take into consideration both the efficacy and the possible side effects of a medicine when choosing therapy, bearing in mind also that no therapy guarantees a total or long-term cure for recurrent aphthous stomatitis.
The results obtained in this study demonstrate the safety and clinical efficacy of a product which, thanks to its unique characteristics, would seem to address fully those requirements of effectiveness, rapidity, tolerability (complete absence of side effects), and convenience (oral administration) that could make it a valid therapeutic option in the treatment of recurrent aphthous stomatitis.