Advanced pharmaceutical bulletin. 15(4):689-690.
doi: 10.34172/apb.025.44040
Letter to Editor
Ozonated Oil for Rheumatic Diseases
Jozélio Freire de Carvalho Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, 1, * 
Ana Tereza Amoedo Martinez Formal analysis, Investigation, Methodology, Validation, 2, 3
Author information:
1Núcleo de Pesquisa em Doenças Crônicas não Transmissíveis (NUPEC), School of Nutrition from the Federal University of Bahia, Salvador, Brazil
2Universidade Estadual de Feira de Santana, Feira de Santana, Brazil
3Novaclin, Grupo CITA, Salvador, Brazil
Copyright and License Information
© 2025 The Author (s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.
Funding Statement
No funding or sponsorship was received for this study or publication of this article.
To Editor,
Ozone therapy has emerged as a highly effective antimicrobial approach, widely used in clinical practice due to its well-documented therapeutic benefits.1 Its primary mechanism of action involves potent oxidizing properties capable of disrupting bacterial cell walls and cytoplasmic membranes, combined with significant anti-inflammatory effects.1 Ozone therapy has also been extensively applied in the management of inflammatory conditions, particularly osteoarthritis (OA). This treatment appears to exert anti-inflammatory and analgesic effects, potentially through the modulation of oxidative stress and the improvement of tissue oxygenation, which together contribute to reduced discomfort and enhanced mobility.2 A recent meta-analysis of eight randomized controlled trials involving 718 participants demonstrated a significant short-term reduction in knee pain within 3 to 6 months following ozone administration.2
Ozone can be delivered via multiple routes, including intra-articular, intramuscular, subcutaneous, rectal, and topical applications using ozonated oil (OzO) (Table 1). To explore the potential of a non-invasive ozone delivery method, we reviewed the literature regarding the use of OzO in rheumatic diseases.
Table 1.
Summary of the main delivery routes used in ozone therapy.
|
Delivery routes
|
Clinical use examples
|
Evidence in osteoarthritis / rheumatic diseases
|
Advantages
|
Limitations / Risks
|
| Intra-articular |
Direct injections into knee or hip |
Meta-analyses: significant pain reduction (3–6 months) |
Rapid local action; strong anti-inflammatory effect |
Invasive procedure; risk of pain or infection |
| Intramuscular / Subcutaneous |
Used occasionally for chronic pain |
Limited evidence |
Easy to apply |
Variable absorption; uncertain systemic effect |
| Rectal (insufflation) |
Applied in inflammatory or systemic conditions |
Rarely studied in OA |
Well tolerated, systemic effect |
Requires equipment; limited patient acceptance |
| Topical (ozonated oil) |
Applied over painful joint, twice daily |
1 RCT (n = 80): significant pain reduction only in severe OA (p = 0.021) |
Non-invasive, safe, home-based use |
Limited evidence; lack of standardized ozone dosage |
| Ozonated water / compresses |
Wounds, ulcers, skin inflammation |
No OA data |
Low cost, safe |
Low stability; mainly restricted to skin/mucosa |
A comprehensive search of PubMed, SciELO, and LILACS databases was conducted, covering publications from 1965 to May 2024, with no language restrictions. Studies were excluded if they were reviews or focused on in vivo or in vitro experiments. After screening titles and abstracts, only one study met the inclusion criteria.
The selected study, conducted by Anzoli et al,3 was a randomized, triple-blind, placebo-controlled trial involving 80 patients with OA (76% female; mean age 64.57 ± 8.83 years). This study evaluated the effects of twice-daily topical application of OzO in 37 OA patients compared with a placebo group of 43 patients over two months. Pain relief was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Visual Analog Scale (VAS). While both groups experienced significant pain reduction, improvements in severe OA were observed exclusively in the OzO-treated group.3 After 60 days, the OzO group improved to about 60 points compared to 68 points in the placebo group, with a significant reduction observed only in severe OA (P = 0.021 vs. P = 0.345, respectively), while mean CRP levels in the OzO group decreased from 14.62 ± 5.75 mg/L to 12.81 ± 5.5 mg/L and in the placebo group from 6.63 ± 2.71 mg/L to 4.37 ± 1.31 mg/L.3 However, the study did not perform quantitative assessments of ozone content in the OzO or in biological samples, precluding determination of the actual ozone concentration associated with the intervention. In clinical practice, OzO is typically applied by gentle massage over the affected joint, typically twice daily for several weeks, and is generally well tolerated.
Regarding mechanisms of action, the anti-inflammatory effects of OzO appear to result from multiple molecular mechanisms. The ozonides and peroxides generated during the ozonation process induce a mild oxidative stress that activates the Nrf2 pathway, leading to the transcription of endogenous antioxidant enzymes (such as SOD, CAT, GPx, and HO-1), while simultaneously inhibiting the pro-inflammatory NF-κB pathway and reducing the expression of cytokines and COX-2.4 Experimental data also indicate that topical OzO reduces key inflammatory mediators, including IL-6, IL-1β, TNF-α, and IFN-γ. Furthermore, OzO has been shown to enhance tissue repair and wound healing by modulating reactive oxygen species (ROS), promoting local growth factor release (e.g., TGF-β, PDGF, VEGF), and improving oxygen supply to the affected tissue.4 Collectively, these pharmacodynamic mechanisms support the rationale for its topical use in inflammatory and degenerative joint conditions.
In conclusion, only one study to date has investigated the effects of OzO in rheumatic diseases, specifically O, reporting improvements in both subjective and objective measures. Based on these findings, future research on OzO should focus on quantifying its ozone-derived compounds, establishing standardized dosages and treatment durations, and conducting long-term, large-scale clinical trials to confirm its efficacy, safety, and underlying the mechanisms of action in OA.
Competing Interests
Authors declare that they have no conflicts of interest.
Data Availability Statement
All data of our study is available at request.
Ethical Approval
The present article performed a literature search and did not need any Ethical approval.
Acknowledgements
Data sharing does not apply to this article, as no datasets were generated or analyzed during the current study.
References
- Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res 2017; 7(3):212-9. doi: 10.4103/2045-9912.215752 [Crossref] [ Google Scholar]
- Arias-Vázquez PI, Tovilla-Zárate CA, Hernández-Díaz Y, González-Castro TB, Juárez-Rojop IE, López-Narváez ML. Short-term therapeutic effects of ozone in the management of pain in knee osteoarthritis: a meta-analysis. PM R 2019; 11(8):879-87. doi: 10.1002/pmrj.12088 [Crossref] [ Google Scholar]
- Anzolin AP, da Silva Collares D, Tadeu Dos Santos R, Pasqualotti A, Rossato-Grando LG, Bertol CD. Effectiveness of topical ozonated oil in severe osteoarthritis: a randomised, triple-blinded, placebo-controlled study. Complement Ther Clin Pract 2021; 43:101351. doi: 10.1016/j.ctcp.2021.101351 [Crossref] [ Google Scholar]
- Sagai M, Bocci V. Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress?. Med Gas Res 2011; 1:29. doi: 10.1186/2045-9912-1-29 [Crossref] [ Google Scholar]