Is the use of ozonated oil effective in the treatment of oral lesions? Systematic review of clinical studies

¿Es el uso del aceite ozonizado efectivo en el tratamiento de las lesiones orales? Una revisión sistemática de estudios clínicos

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The aim of this study was to perform a systematic review (SR) of the therapeutic effect of ozonated oil for oral lesions treatment. A SR was conducted according to the PRISMA guidelines. The Medline (PubMed), Embase, Cochrane Library, Scielo and LILACS were investigated, together with manual searches, to extract all publications until December 2020, including randomized and non-randomized clinical trials reporting the effects of ozonated oils on the management of oral lesions when compared with other methods. The risk of bias (RoB) of the studies included were assessed by using the RoB 2 tool and ROBINS-I. After analyzing the titles and reading the abstracts, 1932 articles were excluded; the remaining 25 passed a full-text evaluation. Ultimately, 13 articles were included in this SR. There was heterogeneity of the results regarding healing times and intervals of ozonated oil application for the treatment of each type of oral lesion, but in general, there was a shorter healing time when ozonated oil was used as therapy, and no adverse effects were reported. Despite the limited information found and the lack of rigorous methodological standards for the use of ozonated oil on oral lesions, a positive effect was suggested. The findings indicated an advantage in terms of shorter healing times when compared with other conventional treatments. No adverse effects were reported, showing safety and reliability for patient’s treatment.

Keywords Mouth; Ozone; Ozoile; Therapeutics; Wounds and injuries

Author and year	Design	N	Age	Gender (M/F)	Type of oral lesion	Test group	Control group (CG)	Assessed parameters	TF	AI	HT SG/CG	AE	Results
Mayor & col. (11) 2010	RCT	90	>15	25/65	pericoronitis	Ozonated oil	50% trichloroacetic acid	Clinical evaluation: satisfactory (improvement or cure at 72h), unsatisfactory (equal to or worse at 72h). Efficacy of the study drug: good (satisfactory clinical evolution), poor (unsatisfactory clinical evolution)	72h	3 times a day	72h/ >72h	no	100% good efficacy for SG (OO), 62% good efficacy and 38% poor efficacy for CG (trichloroacetic acid).
Mayor & col. (12) 2011	RCT	90	>15	Not specified	pericoronitis	Ozonated oil	50% trichloroacetic acid	Microbiological evaluation: satisfactory (field absent or scarce, Gram- not predominant), unsatisfactory (abundant field or covered field, Gram- predominate). Degree of patient satisfaction (satisfied vs not satisfied, according to the patient's appreciation) and adverse effects (yes or no)	72h	3 times a day	72h/ >72h	no	Microbiological evaluation, satisfactory SG in 43 patients (96%), satisfactory CG in 18 patients (40%). Patient’s satisfaction: Satisfactory SG 43 patients (96%), CG 30 patients (66%).
Rodriguez & col. (13) 2012	No RCT	250	<9	82/168	Herpetic gingivo-estomatitis	Ozonated oil	0.1% idoxuridine	Evolution: Cured: When there are no clinical signs of Acute Herpetic Gingivostomatitis. Not cured: When there are clinical signs of Acute Herpetic Gingivostomatitis in the oral cavity	10d	1 time a day	≤8d/ 8a 10d	no	79 patients treated with OO (63.2%) cured in < 6 days, 78 patients treated with iodoxuridine (62.4%) were cured in 9 to 10 days; the treatment with OO minimized the healing time.
Martinez-Abreu & col. (5) 2015	RCT	100	20-59	56/44	Alveolitis	Ozonated oil	Alvogyl	Clinical: recovered (pain and inflammation disappear), improved (pain and inflammation decrease), the same (pain maintains intensity and inflammation persists), worse (pain and inflammation persists or worsens). Microbiological: infected (presence of mopyogens), free of infection (absence of mopyogens Efficacy evaluation: good (clinical criterion of recovered and microbiological free of infection), acceptable (clinical criterion of improved and microbiological free of infection) and poor (clinical criterion of equal or worse and microbiological infected).	7d	Every 72h	3 to 4 days/ >3,4 days	Not specified	100 patients in 2 groups: 50 SG (OO) and 50 CG (alvogyl) The patients were evaluated at 72h (2nd visit), 96h (3rd visit) and at one week of treatment (4th visit). 41 SG patients only needed 2 visits to recover, CG only 29 patients. For the microbiological evaluation: From 20 patients in the SG 13 patients showed signs of recovery from infection, while in the CG from the 20 evaluated patients only 6 showed the same result.
Fontaine& col. (14) 2016	RCT	80	>12	26/54	recurrent aphthous stomatitis	Ozonated oil	vitamins and mouthwash with 0.2% chlorhexidine.	Clinical evaluation: satisfactory (the pain decreases or disappears; the size of the lesion decreases or disappears) not satisfactory (the pain persists and there is no change in the lesion). Healing: cured (there are no clinical signs of stomatitis) and not cured (there are clinical signs of stomatitis in the mucosa).Degree of satisfaction: satisfied and not satisfied (for both criteria the perception of the patients was taken into account).	7d	2 times a day	4 to5 days/ >7 days	no	SG and CG 40 patients each. OS: 34 patients needed only two to three applications to consider a satisfactory clinical evaluation, 38 patients only needed a maximum of 4 to 5 days to consider themselves cured. CG: 18 patients needed more than 7 days. Degree of satisfaction: 97.5% of the GE satisfied.
Castillo & col. (15) 2018	No RCT	68	>19	17/51	subprosthetic stomatitis	Ozonated oil	nystatin	Clinical evaluation, healing was determined as the lesion disappeared and the physiological mucosa became	15d	1 time a day	4 to 12d/ 7 to 15d	no	CG the mucosa recovered normality between 10 to 12 days (52.9% of the sample). Only 14.7% achieved it between 7 and 9 days; no patient was healed during the first week of treatment. SG 44.1% of patients reached normality of the mucosa between 7 to 9 days, 32.4% reached normality between 4 to 6 days. 76.6% of the SG patients healed before 10 days of application.
Diaz-Couso & col. (16) 2018	RCT	32	> 12	12/20.	recurrent aphthous stomatitis	Ozonated oil	alkaline mouthwashes sodium perborate and mouthwashes 0.2% chlorhexidine	Cured, there is a good general condition of the affected area (remission of symptoms) and disappearance of the ulcer. Not cured, permanence of the ulcer, the symptoms do not subside with the application of the medicine. For the criterion of adverse reactions, the presence in the affected area of burning, redness, heat, tumor and pain was taken into account.	7d	4 times a day	3 to 7 days on both groups	no	On the third day, the eight SG patients evolved favorably (50%) and in the CG it was 12.5%. In general the evolution of the treatment, cured patients: SG 93.7% and CG 68.7%.
Jimenez & col. (17) 2018	No RCT	40	> 20	17/23	subprosthetic stomatitis	Ozonated oil	nystatin	Treatment effectiveness: Very effective, effective and not very effective.	7d	1 time a day	4 to days/ >7 days	no	Evaluation of the effectiveness of treatment in sub-prosthesis stomatitis: SG, effective treatment in 14 patients (35.0%), CG, ineffective treatment with 18 patients (45.0%). The daily application of OO was effective for the treatment of this disease between four and seven visits to consultation, healing time was shorter compared to nystatin cream in the CG.
Souto & col. (18) 2018	RCT	100	20-59	Not specified	alveolitis	Ozonated oil	alvogyl	Pain (referred by the patient at the beginning and after the application of the treatments at 5, 15, and 30 minutes, visual analog scale) Inflammation (state of the mucosa surrounding the alveolus, by direct observation: inflamed (hyper-colored, increased in volume, smooth); slightly inflamed (slightly hyper-colored and slight increase in volume) and non-inflamed (normally colored, resilient and normal size). Scarring: non-healing (delayed clot formation, stench, hypersensitivity in the walls of the alveolus), partial scarring (despite the new clot formation, presents hypersensitivity, slight stench) and total scarring (alveolus occupied by a new blood clot) , with formation of granulation tissue and proliferation of the epithelium on the external surface). Response to treatment: no response to treatment (same patient , pain does not disappear, no clot formation, hypersensitive alveolus walls and stench), improved (not intense pain, slight stench and new clot formation) and healed (the clot disappears). pain, clot formed and granulation tissue formation).	7d	1 application	4 to 5d/ >7 d	Not specified	Pain: SG, 40 patients (80%) did not report pain 5 minutes after applying the OO. CG, 13 patients did not report pain 5 minutes after applying the drug, there were statistically significant differences. Grade and inflammation: SG, 40 patients with inflammation at 96 hours after applying the treatment, however, there were no statistically significant differences. Healing: SG, 46 patients (92%) healed at 96h. CG, 44 healed patients (88%). Response to treatment: 86% of SG was cured at 96h and 80% of CG in the same time period.
Leal-Rodríguez & col. (19) 2019	RCT	120	15-35	40/80	recurrent aphthous stomatitis	Ozonated oil	vitamins, diphenhydramine and mouthwash with 0.2% chlorhexidine.	They were evaluated from the clinical point of view the status of the lesions and all the data referring to the time of evolution, to establish the diagnosis and establish treatment	7d	2 times a day	7d / >7d	no	Evaluation on the seventh day: SG, 93.33% cured. CG only 56.67% evolved satisfactorily. Therefore, the time required for the clinical signs of the disease to disappear was shorter when OO was applied than when conventional treatment was applied.
Peña & col. (20) 2019	RCT	60	> 15	Not specified	chronic fibroedematous gingivitis	Ozonated oil	mouthwashes with 0.2% chlorhexidine	The status of the lesions was evaluated from the clinical point of view: healed, improved, equal or worse	6 weeks	2 times a week	6 weeks	no	In both groups, most of the patients evolved satisfactorily during the first 2 weeks of treatment. GE after the fourth visit or week of treatment, it was clinically observed the resolution of all inflammation symptoms in 70% of patients, while in CG 56.6%. In the sixth week in the EG, 96.6% of the cases were given a cure criterion, while in the CG it was 90%.
Alexandrina & col. (21) 2020	No RCT	30	Not specified	Not specified	recurrent aphthous stomatitis	Ozonated oil	Metrogil denta gel (metronidazole 10mg)	Clinical examination, including a survey, clarification of complaints, and a visual examination. For more detail, they used a bacterioscopic study.	14d	4 times a day	3 to 7 days for both groups	Not specified	Compared with traditional dental treatment, the advantage of using OO was noted, on the second day after treatment, patients reported a decrease in pain. The oxygen-ozone irrigation method was less effective. Subjects in the third group, who were treated with Metrogil Denta applications, showed the worst results and clinical improvement was observed between 6 and 7 days after treatment.
Díaz-Couso (22) 2020	No RCT	464	> 12	215/249	Alveolitis, subprosthetic stomatitis, chronic fibromatous gingivitis, recurrent aphthous stomatitis, pericoronitis	Ozonated oil	Subprosthetic stomatitis (Nystatin), recurrent aphthous stomatitis (alkaline sodium perborate mouthwashes and 0.2% chlorhexidine antiseptic rinses), alveolitis (alvogyl), Pericoronitis (0.2% chlorhexidine). Chronic edematous gingivitis (0.2% chlorhexidine mouthwash)	The effectiveness of the treatment was taken into account through its favorable or unfavorable evolution to treatment during seven days, remission of symptoms and / or disappearance of the disease. For the criterion of adverse reactions, the presence of burning, redness, heat, tumor and pain in the affected area was taken into account.	7d	2 times a day	7d / >7d	no	On the third day, SG had a favorable evolution of 97 patients (41.8%); Already on the seventh day there were 209 patients (90.1%). CG on the third day, only 26.2% had evolved favorably, growing to 53.3% on the fifth day. It was observed that on the seventh day there was a total absence of pain and remission of all the symptoms of oral diseases in a greater number of patients, belonging to the SG.

First author (Year)	Title of the paper	Reason for the exclusion
Soler y col (2020)	Application of ozonated sunflower oil in patients affected with chronic fibroedematous gingivitis	Does not present a control group
Frías y col (2020)	Effectiveness of ozone therapy in the treatment of sub-prosthesis stomatitis in Manzanillo 2018-2019.	Does not present a control group
Céspedes y col (2019)	Usefulness of topical Oleozón® in oral ulcers in patients with mechanical artificial ventilation	There is no comparison with conventional therapy
Télles y col (2018)	Use of oleozón® in sub-prosthetic stomatitis	Does not present a control group
Jorge y col (2017)	Effectiveness of oleozón in the treatment of sub-prosthetic stomatitis in patients over 60 years of age.	Does not present a control group
Casado y col (2017)	Effectiveness of oleozon treatment versus aloe vera cream in subprosthetic stomatitis	There is no comparison with conventional therapy
Al-Omiri y col (2016)	Ozone treatment of recurrent aphthous stomatitis; a double blinded study	Does not present a control group
Kumar y col (2016)	Efficacy of Ozonated olive oil in the management of oral lesions and conditions: a clinical trial	Does not present a control group
Milanés y col (2016)	Ozone therapy in sub-prosthesis stomatitis, 2016	Does not present a control group
Armas y col (2015)	Efficacy of two natural therapies in the remission of pain in recurrent aphthous stomatitis	There is no comparison with conventional therapy
Báez y col (2015)	Ozone therapy in a patient with bucal sores	Case Report
Colás-Costa y col	The effectiveness of oleozon in the treatment of recurrent aphthous stomatitis	Does not present a control group

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Facultad de Odontología. Universidad de Costa Rica Ciudad Universitaria Rodrigo Facio, San Pedro, San José, San José, CR, 2060, 2511-8102, 2234-9207 - E-mail: odontos.fo@ucr.ac.cr

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[TFN1] RCT: Randomized clinical trial, No RCT: Non-randomized clinical trial, N: number of participants, M: male, F: female, TF: Time of follow-up, d: Time in days, h: time in hours, AI: Application interval, SG: Study group, CG: Control group, HT: healing time, AE: Adverse effects