Indian Journal of Dermatology
E-IJDŽ-REVIEW ARTICLE
Year
: 2022  |  Volume : 67  |  Issue : 4  |  Page : 479-

Effectiveness and safety of ozone therapy for dermatological disorders: A literature review of clinical trials


Andressa Urbano Machado1, Renata Vidor Contri2,  
1 From the Faculdade de Farmácia, Departamento de Produção de Matéria-Prima; Programa de Pós-Graduação, em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre- RS, Brazil
2 From the Faculdade de Farmácia, Departamento de Produção de Matéria-Prima, Universidade Federal do Rio Grande do Sul, Porto Alegre- RS, Brazil

Correspondence Address:
Renata Vidor Contri
Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre
Brazil

Abstract

Ozone is a strong oxidizing agent, capable of promoting therapeutic effects such as antimicrobial, anti inflammatory, antioxidant and healing activities, with low probability of toxicity when used in a specific dosage range. The aim of this study was to conduct a literature review to assess clinical trials available over the past 10 years regarding the effectiveness and safety of ozone therapy to treat dermatological disorders. The search for bibliographic material was carried out through PubMed, Cochrane Library and Google Scholar electronic databases. The inclusion criteria covered only controlled clinical trials published from 2011 to 2021 and written in English. The 18 selected clinical trials included 1279 patients (ranging from 12 to 400 patients per study), of which 1185 patients were adults and 94 were children. Ozone therapy was evaluated regarding the treatment of diabetic foot ulcers, digital ulcers, chronic venous leg ulcers, atopic dermatitis, skin burns, onychomycosis, tinea pedis, cutaneous leishmaniasis, balanitis xerotica obliterans and multiple common warts. Only three studies, addressing the treatment of cutaneous leishmaniasis, skin ulcers and skin burns, evidenced lack of effectiveness of ozone treatment. Mild adverse effects occurred in three clinical trials, whereas severe side effects occurred in only one clinical trial, regarding skin ulcers. Therefore, ozone therapy may be suggested as an alternative or complementary treatment in some types of dermatological conditions specially affecting refractory patients. Though, a greater number of high-quality clinical trials is needed to clearly establish the safety of ozone therapy in dermatological disorders.



How to cite this article:
Machado AU, Contri RV. Effectiveness and safety of ozone therapy for dermatological disorders: A literature review of clinical trials.Indian J Dermatol 2022;67:479-479


How to cite this URL:
Machado AU, Contri RV. Effectiveness and safety of ozone therapy for dermatological disorders: A literature review of clinical trials. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 29 ];67:479-479
Available from: https://www.e-ijd.org/text.asp?2022/67/4/479/360315


Full Text



 Introduction



The ozone gas (O3) is a strong oxidizing agent with therapeutic properties, such as anti-inflammatory,[1] antioxidant[2] and healing[3],[4] effects, besides activity against bacteria,[5] viruses,[6] fungi,[7] and protozoa.[8] Thus, ozone therapy has been suggested as an alternative treatment in dentistry[9] and in medical fields, such as dermatology. Its use has been proposed in cases of acne, eczema, atopic dermatitis, psoriasis, herpes zoster, pyoderma, mycosis, and also in skin wound healing.[10]

Although some studies evidence ozone toxicity,[11],[12] it is estimated that only chronic exposure (0.7 mg/day) is capable to produce toxic effects due to the constant oxidative stress generation. In contrast, acute exposure to low or moderate levels (1–10 mg/day) generates moderate oxidative stress for a short time, which is able to stimulate the body's antioxidant system without causing injury.[10],[13],[14]

There are three main ways of topically applying ozone: Gaseous ozone, ozone-saturated solutions and ozonized vegetable oils. Gaseous ozone can be administered through a plastic bag containing a mixture of ozone and oxygen, which must cover the affected skin area during the treatment session. Otherwise, ozone hydrotherapy consists of washing the injured skin with ozonized solutions, such as ozonized water, while ozonized vegetable oils can be applied directly to the skin or by the use of dressings. Ozone can also be applied through intravenous, intramuscular, subcutaneous, intradermal, intraarticular and rectal routes of administration.[15],[16] Another form of application is through autohemotherapy, which consists of the removal and ozonation of the patient's blood and subsequent intravenous reintroduction.[15]

In this context, the use of ozone therapy as an alternative dermatological treatment can be proposed, as it could benefit patients who are refractory or intolerant to conventional therapy.[17] Therefore, the aim of this article was to conduct a literature review to assess clinical trials available over the past 10 years regarding the effectiveness and safety of ozone therapy to treat dermatological conditions. The present investigation is the first to propose a compilation of data from current evidence in controlled clinical trials on the risk-benefit of using ozone specifically in dermatology.

 Methodology



The type of review conducted was a literature systematized review. The search for bibliographic material was carried out until December 2021 through PubMed, Cochrane Library and Google Scholar databases using the terms (ozone therapy OR ozonized oils) AND (skin OR dermatology). The inclusion criteria for articles' selection covered only controlled clinical trials with an approach focused on the treatment of skin, hair or nail conditions and articles published from 2011 to 2021. Articles written in languages other than English were excluded.

The methodological quality of the studies was assessed according to the following criteria: Blinded, randomized and controlled clinical trials, treatment period longer than 30 days (in order to evaluate effectiveness and acute toxic side effects) and sample size equal to or greater than the average number of participants involved in all studies (n = 71). Studies that fit these criteria were considered by the review authors to be at lower risk of bias.

 Results



After conducting the literature search and analyzing the articles titles and abstracts, 30 clinical trials approaching the use of ozone therapy to treat dermatological diseases were identified. Among these, 12 studies were excluded for not meeting the inclusion criteria: One study was published in 2002, six studies were written in different languages than English and five studies were conducted without control groups. A total of 18 trials met the inclusion criteria and were selected to compose the present review [Figure 1]. [Figure 2] presents an overview of the included clinical trials and [Table 1] summarizes the most relevant data and main results from each study.[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35]{Figure 1}{Figure 2}{Table 1}

Adverse effects in patients treated with ozone therapy have been reported in 4 of the 18 evaluated clinical trials. Mild adverse effects occurred in three clinical trials,[28],[34],[35] whereas severe side effects occurred in only one trial.[19] In the study conducted by Wainstein et al. (2011),[19] symptoms such as osteomyelitis, fever, wound infection and pulmonary congestion were reported in five patients (8.2%). In the study developed by Lu et al. (2018),[28] only one patient (1.6%) presented skin peeling. Ibrahim et al. (2020)[35] observed symptoms such as pain at the application site, numbness (7.5%) and fatigue (5.0%) in patients who received subcutaneous injections of ozone gas. Aghaei et al. (2019)[34] noticed that some patients treated with ozone had a transient burning sensation at the application site. Moreover, this was the only study that reported adverse effects in the control group (glucantime 20 mg/kg twice daily), including arthralgia, headache and fever.

 Discussion



A general analysis of clinical trials results suggests a positive response to the use of ozone therapy in the investigated dermatological conditions. The patients received ozone therapy by gaseous ozone[18–20,23–26] or incorporated in different vehicles such as water,[22],[28],[30] gel[24] and oil.[21],[27],[28],[29],[30],[31],[33],[34] Only in three clinical trials ozone was not used topically, but were used through subcutaneous,[35] intralesional,[22] intravenous[22],[32] and rectal[32] routes. Only one study used the autohemotherapy procedure with ozone.[32] Otherwise, three interventions associated different routes of administration of injectable ozone with its topical application.[18],[24],[29]

Effectiveness

Considering the outcomes of effectiveness presented in [Table 1], ozone therapy has achieved significantly superior results in statistical analyzes when compared to control groups in the treatment of the following dermatological disorders: Diabetic foot ulcers,[19],[20],[24] chronic venous leg ulcers,[21] digital ulcers,[23],[26] onychomycosis,[27] atopic dermatitis,[29],[30] balanitis xerotica obliterans[33] and multiple common warts.[35] Besides, the studies conducted by Menéndez et al. (2011),[27] Izadi et al. (2019)[24] and Ibrahim et al. (2020)[35] were considered to be at a lower risk of bias in their results analysis compared to the other studies. They met all the following criteria: Blinded, randomized and controlled clinical trials, longer treatment period (30 days or more) and larger sample size (74–400 patients).

Another study approaching the treatment of diabetic foot ulcers reported superior results for ozone therapy (n = 20) in relation to the control group (n = 17), which used the standard treatment (removal of necrotic and purulence-impregnated tissues).[22] However, it is pertinent to report that the authors do not exhibit statistical analyzes that indicate whether this superiority is significant.

Only six studies did not show superiority of ozone treatment when compared to the control groups.[18],[25],[28],[31],[32],[34], however the ozone was considered an interesting alternative treatment in three of them.[18],[28],[31] Hassan et al. (2011)[18] observed that both infrared laser and ozone were effective in promoting the healing of diabetic foot wounds, with similar results. Therefore, ozone therapy could be considered as an alternative to laser treatment. The use of ozone therapy in the treatment of tinea pedis showed similar effectiveness to the treatment with naftinfine associated with ketoconazole, suggesting again the possibility of using ozone as an alternative therapy.[28] Likewise, the trial developed by Campanati et al. (2013)[31] reported a significant decrease in burning sensation, erythema, tension and itching in burned patients treated with ozone and also in the group treated with hyaluronic acid topical gel, without significant differences between the treatments. Therefore, ozone therapy was not inferior to the standard treatment and could be used alternatively. In addition, patients who received ozone therapy presented a significantly less intense hyperpigmentation of healing skin compared to control group (P = 0.03).

Only three studies evidenced lack of effectiveness of ozone therapy.[25],[32],[34] In the trial conducted by Kadir et al. (2020)[25] about skin ulcers, there was no significant difference between treatments in the wound healing assessment, despite a significant reduction in the number of wound bacterial colonies. In the evaluation of ozone therapy to treat skin burns, Martusevich et al. (2018)[32] observed a reduction in levels of endotoxicosis markers and proteinases, an increase in general microcirculation parameters and higher blood antioxidant activity in patients treated with ozone plus standard therapy. However, there were no significant differences reported in relation to the use of standard treatment alone, evidencing that ozone therapy was not effective for the patients observed in this study. In the treatment of cutaneous leishmaniasis, the use of ozone associated with glucantime showed similar results to the use of glucantime alone, suggesting the ineffectiveness of ozone therapy under the conditions of this clinical trial.[34]

Adverse effects

The alternative use of ozone therapy remains controversial due to its potential for toxicity,[11],[12] which is described to occur when criteria such as therapeutic window, exposure time, administration routes and appropriate application methods are not taken into account.[10],[36] The forms of ozone application for which adverse effects were observed include bagging gaseous ozone,[19] ozonized water,[28] ozonized oil[28],[34] and gas subcutaneous injections.[35] Severe symptoms in patients treated with ozone were reported in only one study, conducted by Wainstein et al. (2011).[19] However, according to the authors, there was no causal association between the symptoms and ozone intervention. Skin peeling, reported by Lu et al. (2018),[28] is a mild and possibly expected symptom, since the intervention occurred through topical administration and may be related to the disease course itself. Moreover, this adverse effect disappeared a few days later, probably due to integumentary tissue adaptation to ozone treatment. The pain and numbness at the application site, that was observed by Ibrahim et al. (2020),[35] occurred possibly due to the method of application being performed through subcutaneous injections, a relatively invasive route of administration. In spite of a few clinical trials report the occurrence of adverse effects, in 7 of the 18 studies analyzed, the authors appear not to evaluate the occurrence of unwanted effects during ozone treatment.[18],[20],[22],[23],[25],[26],[32] Thereby, there is a lack of complete data regarding the safety of ozone therapy in these seven investigated clinical trials.

Limitations

Although evidence suggesting ozone therapy effectiveness has been found for most of the clinical trials, several studies presented one or more limitations, such as very small sample size,[30] absence of blinding[18],[21],[22],[23],[25],[26],[29],[30],[32],[33] and randomization,[22],[25],[29],[31],[32],[33] failure to verify homogeneity between the control and treatment groups,[18],[19] inability to reduce variances due to individual characteristics,[30] high rate of loss to follow-up,[19] no long-term follow-up,[20],[23],[25],[26],[30],[32],[33] treatment by different operators at different centers and impossibility of promoting the same standard treatment conditions for all patients due to different economic situations,[24] as well as inability to control environmental factors.[25]

 Conclusion



This is the first review article to compile data from clinical trials on the use of ozone to treat dermatological conditions, which provides a source of evidence that will help in clinical decision-making situations. Since 15 from the 18 selected trials showed the effectiveness of ozone treatment, it may be suggested that ozone therapy could be used as an alternative or complementary treatment in some types of dermatological conditions, such as diabetic foot ulcers, chronic venous leg ulcers, digital ulcers, mycoses, atopic dermatitis, skin burns, balanitis xerotica obliterans and multiple common warts, specially affecting refractory patients. However, based on the available evidence, the use of ozone as a first-choice treatment for dermatological disturbances cannot yet be recommended. There is a dearth of conclusive results on its safety, especially in long-term treatments. Health professionals must evaluate the risk-benefit ratio of this therapy for the patients, considering clinical history, comorbidities and response to conventional therapy. A greater number of high quality, double-blind, randomized and controlled clinical trials is needed to reinforce evidence of effectiveness and clearly establish the safety of ozone therapy in dermatological disorders.

Financial support and sponsorship

The authors thank “Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq” (project number 423066/2018-8) and “Universidade Federal do Rio Grande do Sul”.

Conflicts of interest

There are no conflicts of interest.

References

1Tartari AP, Moreira FF, Pereira MC, Carraro E, Cidral-Filho FJ, Salgado AI, et al. Anti-inflammatory effect of ozone therapy in an experimental model of rheumatoid arthritis. Inflammation 2020;43:985-93.
2Rodríguez ZB, Álvarez RG, Guanche D, Merino N, Rosales FH, Cepero SM, et al. Antioxidant mechanism is involved in the gastroprotective effects of ozonized sunflower oil in ethanol-induced ulcers in rats. Mediators Inflamm 2007;2007:65873.
3Valacchi G, Zanardi I, Lim Y, Belmonte G, Miracco C, Sticozzi C, et al. Ozonated oils as functional dermatological matrices: Effects on the wound healing process using SKH1 mice. Int J Pharm 2013;458:65-73.
4Oğuzkan SB, Kaya ST, Cesur A, Karagül B, Uğraş S, Uğraş HI. Determination of effect on cutaneous wound healing of ozonated hazelnut oil. Proceedings 2018;2:1537.
5Giuliani G, Ricevuti G, Galoforo A, Franzini M. Microbiological aspects of ozone: Bactericidal activity and antibiotic/antimicrobial resistance in bacterial strains treated with ozone. Ozone Ther 2018;3:48-51.
6Petry G, Rossato LG, Nespolo J, Kreutz LC, Bertol CD. In vitro inactivation of Herpes virus by ozone. Ozone Sci Eng 2014;36:249-52.
7Geweely NS. Antifungal activity of ozonized olive oil (Oleozone). Int J Agric Biol 2006;8:670-5.
8Hernández F, Hernández D, Zamora Z, Díaz M, Ancheta O, Rodriguez S, et al. Giardia duodenalis: Effects of an ozonized sunflower oil product (Oleozon) on in vitro trophozoites. Exp Parasitol 2009;121:208-12.
9Suh Y, Patel S, Kaitlyn R, Gandhi J, Joshi G, Smith NL, et al. Clinical utility of ozone therapy in dental and oral medicine. Med Gas Res 2019;9:163-7.
10Schwartz A, Kontorschikova CN, Malesnikov OV, Sánchez GM, Re L, Gribkova IA, et al. Guia Para El Uso Médico Del Ozonio: Fundamentos Terapéuticos e Indicaciones. Asociación Española de Profesionales Médicos en Ozonoterapia, AEPROMO: Madrid; 2011.
11Magzamen S, Moore BF, Yost MG, Fenske RA, Karr CJ. Ozone-related respiratory morbidity in a low-pollution region. J Occup Environ Med 2017;59:624-30.
12Raza A, Dahlquist M, Lind T, Ljungman PLS. Susceptibility to short-term ozone exposure and cardiovascular and respiratory mortality by previous hospitalizations. Environ Heal 2018;17:37.
13Travagli V, Zanardi I, Silvietti A, Bocci V. A physicochemical investigation on the effects of ozone on blood. Int J Biol Macromol 2007;41:504-11.
14Re L, Martínez-Sánchez G, Bordicchia M, Malcangi G, Pocognoli A, Morales-Segura MA, et al. Is ozone pre-conditioning effect linked to Nrf2/EpRE activation pathway in vivo? A preliminary result. Eur J Pharmacol 2014;742:158-62.
15Wang X. Emerging roles of ozone in skin diseases. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43:114-23.
16Travagli V, Zanardi I, Bocci V. Topical applications of ozone and ozonated oils as anti-infective agents: An insight into the patent claims. Recent Pat Antiinfect Drug Discov 2009;4:130-42.
17Clavo B, Santana-Rodriguez N, Gutierrez D, Lopez JC, Suarez G, Lopez L, et al. Long-term improvement in refractory headache following ozone therapy. J Altern Complement Med 2013;19:453-8.
18HHassan AS, Zakarya O, Al Sheimy WM, Eldin NE. Therapeutic effecacy of ozone and low level laser in treatment of diabetic foot ulcers. Zagazig Med J 2011;17:109-22.
19Wainstein J, Feldbrin Z, Boaz M, Harman-Boehm I. Efficacy of ozone-oxygen therapy for the treatment of diabetic foot ulcers. Diabetes Technol Ther 2011;13:1255-60.
20Zhang J, Guan M, Xie C, Luo X, Zhang Q, Xue Y. Increased growth factors play a role in wound healing promoted by noninvasive oxygen-ozone therapy in diabetic patients with foot ulcers. Oxid Med Cell Longev 2014;2014:273475.
21Solovąstru LG, Stîncanu A, De Ascentii A, Capparé G, Mattana P, Vâţă D. Randomized, controlled study of innovative spray formulation containing ozonated oil and α-bisabolol in the topical treatment of chronic venous leg ulcers. Adv Ski Wound Care 2015;28:406-9.
22Teuvov AA, Baziev AM, Lovpache ZN, Teunikova IS, Chudopal SM. Ozone therapy in the comprehensive treatment of diabetic foot syndrome. Biomed Pharmacol J 2017;10:1871-8. doi: 10.13005/bpj/1306
23Hassanien M, Rashad S, Mohamed N, Elawamy A, Ghaly MS. Non-invasive oxygen-ozone therapy in treating digital ulcers of patients with systemic sclerosis. Acta Reumatol Port 2018;43:210-6.
24Izadi M, Kheirjou R, Mohammadpour R, Aliyoldashi MH, Moghadam SJ, Khorvash F, et al. Efficacy of comprehensive ozone therapy in diabetic foot ulcer healing. Diabetes Metab Syndr 2019;13:822-5.
25Kadir K, Syam Y, Yusuf S, Zainuddin M. Ozone therapy on reduction of bacterial colonies and acceleration of diabetic foot ulcer healing. Home Healthc Now 2020;38:215-20.
26Kaymaz S, Karasu U, Alkan H, Ulutaş F, Yaşar CA, Ök ZD, et al. Efficacy of local oxygen-ozone therapy for the treatment of digital ulcers refractory to medical therapy in systemic sclerosis: A randomized controlled study. Mod Rheumatol 2021;roab117. doi: 10.1093/mr/roab117. Online ahead of print.
27Menéndez S, Falcón L, Maqueira Y. Therapeutic efficacy of topical OLEOZON® in patients suffering from onychomycosis. Mycoses 2011;54:272-7.
28Lu J, Guo M, Ligui H, Wu K, Xiang Y, Huang J, et al. Efficacy of combination of ozonated water with oil for treatment of tinea pedis. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43:147-51.
29Illek YY, Zaytseva GA, Galanina AV, Vasilieva YA, Rybakova TN, Suslova EY. Immunomodulating and anti-relapse effects of ozone therapy in atopic dermatitis in preschool and primary school children. Sovrem Tehnol v Med 2013;5:89-91.
30Zeng J, Dou J, Gao L, et al. Topical ozone therapy restores microbiome diversity in atopic dermatitis. Int Immunopharmacol 2020;80:106191.
31Campanati A, De Blasio S, Giuliano A, Xiang Y, Huang J, Ding S, et al. Topical ozonated oil versus hyaluronic gel for the treatment of partial- to full-thickness second-degree burns: A prospective, comparative, single-blind, non-randomised, controlled clinical trial. Burns 2013;39:1178-83.
32Martusevich AK, Peretyagin SP, Ruchin MV, Struchkov AA. Ozone therapy in patients with burn disease. J Biomed Sci Eng 2018;11:27-35.
33Currò M, Russo T, Ferlazzo N, Caccamo D, Antonuccio P, Arena S, et al. Anti-inflammatory and tissue regenerative effects of topical treatment with ozonated olive oil/Vitamin E acetate in balanitis xerotica obliterans. Molecules 2018;23:645.
34Aghaei M, Aghaei S, Sokhanvari F, Ansari N, Hosseini SM, Mohaghegh M-A, et al. The therapeutic effect of ozonated olive oil plus glucantime on human cutaneous leishmaniasis. Iran J Basic Med Sci 2019;22:25-30.
35Ibrahim AM, Elkot RA, Khashaba SA. Successful treatment of multiple common warts with intralesional ozone. Dermatologic Surg 2020;46:928-33.
36Schwartz A, Sánchez GM, Sabah F. Madrid Declaration On Ozone Therapy. 2nd ed. International Scientific Committee of Ozone Therapy (ISCO3): Madrid; 2015.