Ozone Therapy for Arthritis: Clinical Evidence for Joint Pain and Inflammation

Ozone Therapy for Arthritis: What the Clinical Evidence Shows

Arthritis affects hundreds of millions of people worldwide, causing progressive joint pain, stiffness, and disability. The two most common forms, osteoarthritis (OA) and rheumatoid arthritis (RA), involve different underlying mechanisms but share a common thread: chronic inflammation that damages joint tissues over time. [1,2]

OA results from the gradual breakdown of cartilage in weight-bearing joints like the knees and hips. RA, on the other hand, is an autoimmune condition where the immune system attacks the joint lining, leading to swelling, pain, and eventual joint destruction. [2,3]

Standard treatments for both conditions, including pain medications, corticosteroid injections, and disease-modifying drugs, often provide incomplete relief. Many carry significant side effects with long-term use. This has driven clinicians and researchers to investigate ozone therapy as a complementary or alternative approach. [4,5]

Over the past two decades, a growing body of clinical research has examined intra-articular ozone injections for knee OA, with multiple randomized controlled trials, systematic reviews, and meta-analyses now available. The evidence for RA is earlier-stage but includes promising preclinical and clinical data on ozone's ability to modulate the immune response and reduce inflammatory markers. [6,7,3]

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

Types of Ozone Therapy for Arthritis

Medical ozone is a gas mixture of oxygen (O2) and ozone (O3) used to treat arthritis through several delivery routes. The two most common approaches are intra-articular injections, where the gas is delivered directly into the joint space, and systemic routes like major autohemotherapy (MAH) and rectal insufflation.[1,8,6] In addition, there is a clinical study of 80 elderly patients demonstrating that massaging ozone oil into the joint twice a day can relieve pain in severe osteoarthritis. [9]

Ozone and ozonides function as bioregulators that can turn on anti-inflammatory, analgesic (pain-relieving), and antioxidant pathways in the body. [1,8,6] Rather than simply masking symptoms, it modulates the body's inflammatory and oxidative stress pathways at a cellular level. [10,3]

Glossary of Terms

If you are new to ozone therapy research, here are the key terms you will encounter throughout this article:

• Intra-articular injection: Injection of ozone-oxygen gas mixture into the joint space using a needle, typically guided by ultrasound for precision.
• Osteoarthritis (OA): A degenerative joint disease involving the gradual wearing away of cartilage, the smooth tissue that covers the ends of bones in a joint. It is the most common form of arthritis worldwide. [11]
• Rheumatoid arthritis (RA): An autoimmune disease in which the body's immune system attacks the synovial membrane (joint lining), causing chronic inflammation, pain, and eventual joint damage. [3]
• Visual Analog Scale (VAS): A 0 to 10 pain rating scale commonly used in clinical trials, where 0 means no pain and 10 means the worst pain imaginable. You will see VAS scores referenced frequently in ozone therapy studies. [12]
• WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index): A standardized questionnaire that measures three dimensions of arthritis impact: pain, stiffness, and physical function. Lower WOMAC scores indicate better outcomes. [12]

How Does Ozone Therapy Help with Arthritis?

Ozone therapy targets arthritis through three interconnected mechanisms: reducing inflammation, relieving pain, and protecting cartilage. Each mechanism has a growing body of preclinical and clinical evidence behind it.

Reducing Joint Inflammation and Oxidative Stress

Chronic inflammatory joint diseases like rheumatoid arthritis (RA) and osteoarthritis (OA) share a common feature: high oxidative stress combined with a blocked antioxidant response. This creates a vicious cycle where inflammation feeds more inflammation.

By activating Nrf2, ozone essentially shifts cells out of their pro-inflammatory state and restores normal redox balance. This is not a suppression of the immune system, it is a recalibration. [10]

Cytokine modulation provides the measurable downstream effect of this redox shift. In a preclinical study (N=30 male Wistar rats with induced RA), intra-articular ozone injections significantly reduced three key inflammatory markers:

• TNF-α (tumor necrosis factor alpha, a driver of joint destruction)
• IL-1β (interleukin-1 beta, which promotes cartilage breakdown)
• IL-6 (interleukin-6, which amplifies systemic inflammation)

The ozone-treated group showed decreased joint swelling and cartilage erosion compared to controls. [13]

Additional rat studies confirm this cytokine-lowering effect. In a study of 40 rats with RA, intra-articular ozone at different concentrations reduced TNF-α levels in both serum and synovial tissue, with effects varying by concentration. [60] Another preclinical trial in rats with peptidoglycan-polysaccharide-induced arthritis found that ozone treatment reduced pro-inflammatory cytokines and oxidative stress markers while ameliorating joint damage. [14]

Key takeaway: Ozone does not simply mask inflammation. It resets the underlying redox imbalance that drives chronic joint disease. [MODERATE evidence, preclinical]

Selective response in RA vs. OA: A 2024 study comparing medical ozone's effects in RA and OA patients found that RA patients exhibit a more significant improvement in oxidative stress biomarkers than OA patients. [3] This makes biological sense. RA involves higher systemic baseline inflammation and oxidative stress, so there is more room for redox regulation to make a measurable difference. [3]

This selectivity suggests that ozone therapy may be particularly well-suited as an adjunct treatment in high-inflammation joint conditions like RA, where it has been shown to increase the clinical response to methotrexate (a standard RA drug) while improving cellular redox balance. [15,16]

Pain Relief and Analgesic Effects

Pain in arthritic joints comes from multiple sources: inflammatory cytokines irritating nerve endings, hypoxic (oxygen-starved) tissue, and mechanical damage. Ozone addresses at least two of these.

Analgesic pathways of ozone in arthritis include:

• Cytokine reduction at the joint site, which decreases chemical irritation of pain receptors [8,6]
• Improved local oxygen delivery to hypoxic tissues surrounding the joint [8,6]
• Anti-inflammatory effects that reduce swelling and pressure on nerves [17]
• Antinociceptive effects that reduce pain signaling via voltage-gated sodium channels [18]

The clinical evidence for pain relief is substantial. Multiple systematic reviews and meta-analyses of randomized controlled trials confirm that intra-articular ozone significantly reduces VAS pain scores in knee OA patients. [19,20,21,22,7]

Here is what the major reviews found:

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A 2025 double-blind RCT (N=75 patients, three arms) compared intra-articular ozone at 20 mcg/mL vs. 40 mcg/mL vs. sham injection for knee OA. Both ozone concentrations significantly reduced pain and improved functional mobility compared to sham, confirming the analgesic effect in a rigorous placebo-controlled design. [24]

Cartilage Protection, Regeneration, and Adjunctive Use

Beyond symptom relief, there is preliminary evidence that ozone may help protect and even regenerate damaged cartilage.

Chondrocyte support: At low concentrations, ozone may stimulate chondrocyte activity (the cells responsible for producing and maintaining cartilage) and promote cartilage matrix production. [11] A 2016 review of the available evidence concluded that medical ozone therapy shows potential as a treatment modality for regeneration of damaged articular cartilage in OA. [11]

A 2025 study on temporomandibular joint OA found that ozone therapy protected cartilage degeneration by reducing the expression of matrix metalloproteinases (MMPs), the enzymes that break down cartilage tissue. [25]

An injectable ozone-rich nanocomposite hydrogel study (preclinical, 2024) demonstrated both anti-inflammatory and cartilage-protective effects in OA treatment, suggesting that sustained ozone delivery to the joint may enhance these regenerative benefits. [26]

Evidence badge: [PRELIMINARY] Cartilage regeneration claims are based primarily on preclinical and mechanistic studies. Human trials measuring structural cartilage changes are still needed.

Multimodal success: Ozone therapy appears to work best when combined with other treatments rather than used alone. A 2023 network meta-analysis of RCTs found that combining intra-articular injections with physical therapy yielded superior pain and function outcomes compared to single-modality treatments for knee OA. [27]

This aligns with findings from other combination studies:

• Ozone + hyaluronic acid outperformed hyaluronic acid alone for pain relief in a 2025 RCT (N=60 patients). The combination group received 10 mL of ozone at 30 mcg/mL plus HA, showing greater pain reduction than HA alone. [28]
• Ozone combined with physical therapy and exercise produced better functional outcomes than injections alone. [27,29]
• A 2024 study found that ozone as an adjunct treatment enhanced therapy outcomes in knee OA patients. [30]

Bottom line: Ozone therapy for arthritis works through complementary mechanisms: calming inflammation, reducing pain signals, and potentially supporting cartilage health. The strongest evidence supports its use as part of a multimodal treatment plan rather than a standalone therapy.

For a deeper look at specific protocols and dosing used in clinical trials, download our complete guide to ozone therapy for joint conditions.

Clinical Evidence for Ozone Injection Therapy in Knee Osteoarthritis

Knee osteoarthritis has the largest body of clinical evidence for ozone injection therapy of any joint condition. Multiple randomized controlled trials, systematic reviews, and meta-analyses have evaluated intra-articular ozone injections head-to-head against placebos, hyaluronic acid, corticosteroids, platelet-rich plasma, and exercise therapy.

Evidence Level: [STRONG] Multiple RCTs and meta-analyses consistently support intra-articular ozone injections for pain relief and functional improvement in knee osteoarthritis.

Clinical Trials Evidence Table

The table below summarizes key randomized controlled trials evaluating intra-articular ozone injections for knee osteoarthritis. Each trial used a different comparator, giving a broad picture of how ozone stacks up against standard treatments.

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Bottom line: The weight of evidence from at least 8 systematic reviews and meta-analyses consistently supports intra-articular ozone injections as an effective treatment for knee osteoarthritis pain and functional limitation. Ozone performs comparably to hyaluronic acid and may serve as a lower-cost alternative.

What does this mean for you? If you have knee osteoarthritis and are exploring non-surgical options, the clinical evidence for ozone injections is very strong. The research consistently shows meaningful pain reduction and improved joint function, with ozone performing on par with hyaluronic acid in head-to-head comparisons.

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

Ozone Treatment for Rheumatoid Arthritis and Other Joint Conditions

Most ozone therapy research in arthritis focuses on osteoarthritis. But rheumatoid arthritis (RA), gouty arthritis, and temporomandibular joint (TMJ) disorders also involve chronic inflammation and joint destruction. A smaller but growing body of evidence suggests ozone therapy may help with these conditions too.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis is an autoimmune disease where the immune system attacks the joint lining. This triggers chronic inflammation, pain, and progressive joint destruction. The inflammatory cascade in RA involves elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), two cytokines (immune signaling molecules) that drive tissue damage.

Preclinical Evidence

Preclinical work supports an anti-inflammatory pattern. In a rat model using peptidoglycan-polysaccharide (PG/PS)-induced arthritis, ozone oxidative postconditioning reduced pro-inflammatory cytokines and oxidative stress while improving joint damage scores. [14]

Another rat study (N=48) examined intra-articular ozone injections at different concentrations and found that ozone regulated TNF-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) levels in both serum and synovial tissue. This points to ozone's ability to modulate the TNF signaling, the same pathway targeted by biologic drugs used in RA treatment. [39]

Clinical Redox Balance

Oxidative stress plays a central role in RA. The disease creates a vicious cycle: inflammation generates reactive oxygen species (ROS), which damage tissues and trigger more inflammation. Breaking this cycle is one of the goals of RA treatment.

A 2016 clinical study by León Fernández and colleagues specifically measured how medical ozone affected RA patients already taking methotrexate. The results showed that adding ozone therapy:

• Increased methotrexate's clinical response
• Improved cellular redox balance in RA patients

This means patients responded better to their existing medication when ozone was added as an adjunct therapy. [15]

A broader study of elderly patients (ages 60–70) with oxidative-etiology diseases found that medical ozone arrested oxidative damage progression and regulated vasoactive mediator levels. While not exclusively focused on RA, this supports the concept that ozone restores redox balance in conditions driven by chronic oxidative stress. [40]

Bottom line: Clinical evidence indicates ozone therapy improves redox balance in RA patients and enhances the effectiveness of standard medications like methotrexate. [MODERATE evidence — clinical]

Mechanism: The Adenosine Pathway

How does ozone enhance methotrexate's effects? A 2025 review by León Fernández and colleagues proposed a shared mechanism involving adenosine, a molecule with powerful anti-inflammatory properties.

Here is how the pathway works:

• Methotrexate increases extracellular adenosine levels, which suppresses inflammation.
• Medical ozone also increases adenosine signaling through its effects on cellular redox pathways.
• When combined, the two therapies amplify each other's anti-inflammatory effects through this shared adenosine-mediated mechanism.

The review analyzed pharmacological trials involving ozone in disease models alongside clinical responses in RA patients. The authors concluded that ozone and methotrexate converge on the adenosine pathway, providing a molecular explanation for why the combination works better than methotrexate alone.[16]

Bottom line: Ozone and methotrexate share an adenosine-mediated anti-inflammatory mechanism, which may explain why combining them improves clinical outcomes in RA. [PRELIMINARY evidence — mechanistic review]

Gouty Arthritis

Gouty arthritis occurs when monosodium urate crystals deposit in joints, triggering intense inflammation and debilitating pain. Gout attacks are among the most painful forms of acute arthritis.

A 2024 review identified ozone therapy as an emerging treatment for managing the acute inflammation caused by urate crystal deposition, although specific clinical trial data remains limited. [41] 

[LIMITED evidence — narrative review]

TMJ Osteoarthritis

Temporomandibular joint osteoarthritis (TMJ-OA) causes progressive cartilage breakdown, jaw pain, and difficulty with basic activities like chewing and talking. The TMJ is a small, complex joint, and treatment options are limited.

A 2020 review noted that ozone injections were an effective treatment option for reducing pain and improving jaw function, although more trials are needed. [42] The most recent evidence comes from a 2025 animal study that investigated ozone therapy's protective effects on cartilage in TMJ osteoarthritis. The researchers focused on matrix metalloproteinases (MMPs), enzymes that break down cartilage and drive joint degeneration. Results showed that:

• Ozone therapy modulated the expression of MMP-2 and other MMPs involved in cartilage degradation.
• The treatment protected against cartilage degeneration in TMJ-OA. [25]

Bottom line: Ozone injections for TMJ osteoarthritis reduce pain and may protect cartilage by modulating the enzymes (MMPs) that drive joint breakdown. [MODERATE evidence — preclinical + reviews]

Some practitioners also use ozone ear insufflation empirically to deliver ozone near the jaw joints for TMJ dysfunction. However, there is currently no published clinical evidence for this delivery.

Ozone Therapy Protocols for Arthritis

Intra-Articular Protocol (Knee OA)

A clinician injects a precise volume of oxygen-ozone gas directly into the joint space under sterile conditions, typically via an anterolateral or anteromedial approach.[1] 

Here are the key parameters used across clinical trials:

• Concentration: Most randomized controlled trials use 20 to 30 mcg/mL of ozone gas. [20,12]
• Volume: 10 to 20 mL of oxygen-ozone gas mixture per joint per session. [12,21]
• Frequency: Typically once per week for 3 to 8 sessions, depending on the trial design and severity of osteoarthritis. [31,12]
• Technique: Sterile needle injection via the anterolateral or anteromedial portal of the knee, sometimes guided by ultrasound for precision. [1,32]

Multiple systematic reviews and meta-analyses confirm that these intra-articular protocols consistently reduce pain scores (VAS and WOMAC) across trials. [20,21,22,7,38] [STRONG]

For a complete breakdown of intra-articular ozone protocols and step-by-step guidance, download our free protocol guide.

Systemic Protocols for Autoimmune Arthritis

Autoimmune forms of arthritis like RA involve systemic immune dysregulation, not just local joint damage. That means local injections alone may not address the underlying inflammatory cascade. Systemic ozone protocols aim to rebalance the body's redox status and modulate immune function throughout the entire system. 

Major Autohemotherapy (MAH)

MAH is the most commonly studied systemic ozone protocol for inflammatory conditions. [43] In this procedure:

• A clinician draws 100 to 200 mL of the patient's venous blood into a sterile container.
• The blood is mixed with an oxygen-ozone gas mixture at a concentration of 40 to 60 mcg/mL.
• The ozonated blood is then reinfused intravenously.

Rectal Insufflation

Rectal insufflation offers an alternative systemic route for those with difficulty getting major autohemotherapy or needs more frequent treatments.

Both MAH and rectal insufflation are recognized systemic routes in the ISCO3 Madrid Declaration and WFOT clinical guidelines for managing chronic inflammatory and autoimmune conditions.

Contraindications

Ozone therapy for arthritis is generally well tolerated across clinical trials, but certain medical conditions represent absolute contraindications. These apply to both intra-articular and systemic protocols. [1,8]

Absolute contraindications include:

• G6PD deficiency (favism): Patients lacking the glucose-6-phosphate dehydrogenase enzyme cannot handle the oxidative stress from ozone exposure. This can trigger hemolytic anemia, a potentially life-threatening reaction. [8]
• Uncompensated hyperthyroidism: The increased metabolic rate in uncontrolled hyperthyroidism makes patients more vulnerable to oxidative damage. [1,8]
• Active hemorrhage or severe coagulopathy: Ozone can affect platelet aggregation, making it unsafe during active bleeding or in patients with severe clotting disorders. [8]
• Pregnancy: Due to insufficient safety data, ozone therapy is contraindicated during pregnancy. [1,8]

Important: Any patient considering ozone therapy for arthritis should be screened for G6PD deficiency before treatment. This is a simple blood test that rules out the most serious potential adverse reaction.

Additional relative precautions may apply depending on the specific protocol and the patient's overall health status. A qualified practitioner trained in medical ozone therapy should evaluate each case individually.

Frequently Asked Questions

What are the benefits of ozone therapy for arthritis?

Ozone therapy offers two primary benefits for arthritis patients: pain reduction and functional improvement. [STRONG evidence for knee OA]

How does ozone compare to hyaluronic acid?

Hyaluronic acid (HA) is one of the most widely used intra-articular injections for knee OA. Multiple head-to-head comparisons show that ozone performs similarly. [19] [STRONG] 

Where ozone may have an edge is at the molecular level, as a randomized controlled trial by Sconza et al. (2023) compared ozone therapy to HA injections in knee OA patients and found that ozone had a stronger effect on reducing synovial inflammatory markers, including pro-inflammatory cytokines in the joint fluid. [20]

Is ozone therapy safe for joints?

In clinical trials, intra-articular ozone therapy has a favorable safety profile. [STRONG]

The most commonly reported side effect is mild, transient pain at the injection site, which typically resolves within hours. No serious adverse events were reported in major systematic reviews of ozone therapy for knee OA. [20,6] 

Can ozone be used for rheumatoid arthritis?

Yes. While most ozone-for-arthritis research focuses on osteoarthritis, a growing body of evidence supports ozone therapy as a systemic redox regulator in rheumatoid arthritis. [MODERATE]

Conclusion

Intra-articular ozone injections for knee osteoarthritis stand on some of the strongest clinical evidence, establishing ozone as a legitimate alternative to HA for knee OA management. [19]

This matters because ozone is significantly less expensive than hyaluronic acid and platelet-rich plasma. [31] 

Safety data across trials is equally reassuring, as no major adverse events have been established using intra-articular ozone injections for knee OA.

The evidence for ozone in rheumatoid arthritis is still developing but mechanistically compelling. Ozone acts as a bioregulator to restore cellular redox balance, which distinguishes it from conventional anti-inflammatory agents that suppress immune function broadly. [3]

Here is a summary of the current evidence landscape across arthritis subtypes:

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For clinicians and patients exploring non-surgical options for joint pain, intra-articular ozone therapy represents a well-studied, low-risk intervention for knee OA. For systemic and autoimmune joint conditions like RA, the mechanistic rationale is strong, and clinical research continues to build.

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

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References:

1 Jeyaraman, M., Jeyaraman, N., Ramasubramanian, S., Balaji, S., Nallakumarasamy, A., Patro, B. P., et al. (2024) Ozone therapy in musculoskeletal medicine: a comprehensive review. Eur. J. Med. Res., Springer Science and Business Media LLC 29, 398

2 Rezuş, E., Burlui, A., Cardoneanu, A., Macovei, L. A., Tamba, B. I. and Rezuş, C. (2021) From pathogenesis to therapy in knee osteoarthritis: Bench-to-bedside. Int. J. Mol. Sci., MDPI AG 22, 2697

3 León Fernández, O. S., Oru, G. T., Viebahn-Haensler, R., López Cabreja, G., Serrano Espinosa, I. and Corrales Vázquez, M. E. (2024) Medical ozone: A redox regulator with selectivity for rheumatoid arthritis patients. Pharmaceuticals (Basel), Multidisciplinary Digital Publishing Institute 17, 391

4 Ding, J. B. and Hu, K. (2021) Injectable therapies for knee osteoarthritis. Reumatologia, Termedia Sp. z.o.o. 59, 330–339

5 Bahari Golamkaboudi, A., Vojoudi, E., Babaeian Roshani, K., Porouhan, P., Houshangi, D. and Barabadi, Z. (2024) Current non-surgical curative regenerative therapies for knee osteoarthritis. Stem Cell Rev Rep, Springer Science and Business Media LLC 20, 2104–2123

6 Liu, Q., Liu, J., Cao, G., Liu, Y., Huang, Y. and Jiang, X. (2025) Ozone therapy for knee osteoarthritis: a literature visualization analysis of research hotspots and prospects. Med. Gas Res., Ovid Technologies (Wolters Kluwer Health) 15, 356–365

7 Lino, V. T. S., Marinho, D. S., Rodrigues, N. C. P. and Andrade, C. A. F. (2024) Efficacy and safety of ozone therapy for knee osteoarthritis: an umbrella review of systematic reviews. Front. Physiol., Frontiers Media SA 15, 1348028

8 Elvis, A. M. and Ekta, J. S. (2011) Ozone therapy: A clinical review. J. Nat. Sci. Biol. Med. 2, 66–70

9 Anzolin, A. P., Collares, D. da S., Tadeu Dos Santos, R., Pasqualotti, A., Rossato-Grando, L. G. and Bertol, C. D. (2021) Effectiveness of topical ozonated oil in severe osteoarthritis: A randomised, triple-blinded, placebo-controlled study. Complement. Ther. Clin. Pract. 43, 101351

10 Viebahn-Haensler, R. and León Fernández, O. S. (2021) Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int. J. Mol. Sci. 22 https://doi.org/10.3390/ijms22157890

11 Manoto, S. L., Maepa, M. J. and Motaung, S. K. (2018) Medical ozone therapy as a potential treatment modality for regeneration of damaged articular cartilage in osteoarthritis. Saudi J. Biol. Sci., Elsevier BV 25, 672–679

12 Lopes de Jesus, C. C., Dos Santos, F. C., de Jesus, L. M. O. B., Monteiro, I., Sant’Ana, M. S. S. C. and Trevisani, V. F. M. (2017) Comparison between intra-articular ozone and placebo in the treatment of knee osteoarthritis: A randomized, double-blinded, placebo-controlled study. PLoS One, Public Library of Science (PLoS) 12, e0179185

13 Tartari, A. P. S., Moreira, F. F., Pereira, M. C. D. S., Carraro, E., Cidral-Filho, F. J., Salgado, A. I., et al. (2020) Anti-inflammatory effect of ozone therapy in an experimental model of rheumatoid arthritis. Inflammation, Springer Science and Business Media LLC 43, 985–993

14 Vaillant, J. D., Fraga, A., Díaz, M. T., Mallok, A., Viebahn-Hänsler, R., Fahmy, Z., et al. (2013) Ozone oxidative postconditioning ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats. Eur. J. Pharmacol., Elsevier BV 714, 318–324

15 León Fernández, O. S., Viebahn-Haensler, R., Cabreja, G. L., Espinosa, I. S., Matos, Y. H., Roche, L. D., et al. (2016) Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. Eur. J. Pharmacol., Elsevier BV 789, 313–318

16 León Fernández, O. S., Oru, G. T., Viebahn-Haensler, R., López Cabreja, G., Serrano Espinosa, I. and Corrales Vázquez, M. E. (2025) Medical ozone increases methotrexate effects in rheumatoid arthritis through a shared new mechanism which involves adenosine. Int. J. Mol. Sci., MDPI AG 26, 5256

17 de Sire, A., Marotta, N., Ferrillo, M., Agostini, F., Sconza, C., Lippi, L., et al. (2022) Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review. Int. J. Mol. Sci. 23 https://doi.org/10.3390/ijms23052528

18 Masiello, G., Franzini, M., Richelmi, T., Tirelli, U., Valdenassi, L. and Chirumbolo, S. (2025) Ozone therapy addresses neuropathic pain in ulcerous wounds. Med. Gas Res., Ovid Technologies (Wolters Kluwer Health) 15, 448–449

19 Migliorini, F., Giorgino, R., Mazzoleni, M. G., Schäfer, L., Bertini, F. A. and Maffulli, N. (2024) Intra-articular injections of ozone versus hyaluronic acid for knee osteoarthritis: a level I meta-analysis. Orthop. Traumatol., Springer Science and Business Media LLC 35, 20

20 Sconza, C., Respizzi, S., Virelli, L., Vandenbulcke, F., Iacono, F., Kon, E., et al. (2020) Oxygen-ozone therapy for the treatment of knee osteoarthritis: A systematic review of randomized controlled trials. Arthroscopy, Wiley 36, 277–286

21 Raeissadat, S. A., Tabibian, E., Rayegani, S. M., Rahimi-Dehgolan, S. and Babaei-Ghazani, A. (2018) An investigation into the efficacy of intra-articular ozone (O2-O3) injection in patients with knee osteoarthritis: a systematic review and meta-analysis. J. Pain Res., Dove Medical Press Ltd. 11, 2537–2550

22 Noori-Zadeh, A., Bakhtiyari, S., Khooz, R., Haghani, K. and Darabi, S. (2019) Intra-articular ozone therapy efficiently attenuates pain in knee osteoarthritic subjects: A systematic review and meta-analysis. Complement. Ther. Med., Elsevier BV 42, 240–247

23 Oliviero, A., Giordano, L. and Maffulli, N. (2019) The temporal effect of intra-articular ozone injections on pain in knee osteoarthritis. Br. Med. Bull., Oxford University Press (OUP) 132, 33–44

24 Arjmanddoust, Z., Nazari, A. and Moezy, A. (2025) Efficacy of two doses of intra-articular ozone therapy for pain and functional mobility in knee osteoarthritis: a double-blind randomized trial. Adv. Rheumatol., Springer Science and Business Media LLC 65, 11

25 Machado, T. T., Machado, A. C. S., Nishijima, C. M., de Andrade, C. R., Consonni, S. R., de Sousa, L. M., et al. (2025) Protective effects of ozone therapy on cartilage degeneration in temporomandibular joint osteoarthritis. Inflammopharmacology, Springer Science and Business Media LLC 33, 5333–5345

26 Wu, H., Wang, J., Lin, Y., He, W., Hou, J., Deng, M., et al. (2024) Injectable ozone-rich nanocomposite hydrogel loaded with D-mannose for anti-inflammatory and cartilage protection in osteoarthritis treatment. Small, Wiley 20, e2309597

27 Liao, C.-D., Chen, H.-C., Huang, M.-H., Liou, T.-H., Lin, C.-L. and Huang, S.-W. (2023) Comparative efficacy of intra-articular injection, physical therapy, and combined treatments on pain, function, and sarcopenia indices in knee osteoarthritis: A network meta-analysis of randomized controlled trials. Int. J. Mol. Sci., MDPI AG 24, 6078

28 Akhavanakbari, G., Asayeshi, M., Noktehsanj, R. and Aslani, M. R. (2025) Comparing the efficacy of combining ozone therapy with hyaluronic acid versus using hyaluronic acid alone for pain relief in patients with knee osteoarthritis: A randomized clinical trial. Complement. Ther. Med., Elsevier BV 93, 103238

29 Nazarieh, M., Ghannadi, S., Halabchi, F., Maleklou, F., Ejtehadi, F., Ehsani Kouhikheili, S. R., et al. (2024) The effect of intra-articular ozone injection combined with home-based exercise on pain and function in daily living activities of patients with mild to moderate knee osteoarthritis, a randomized double-blinded controlled clinical trial. J. Bodyw. Mov. Ther., Elsevier BV 38, 541–548

30 Valdenassi, L., Chierchia, M., Pandolfi, S., Bellardi, D., Chirumbolo, S. and Franzini, M. (2024) Adjunct treatment with ozone to enhance therapy of knee osteoarthritis: preliminary results. Clin. Rheumatol., Springer Science and Business Media LLC 43, 2093–2101

31 Raeissadat, S. A., Ghazi Hosseini, P., Bahrami, M. H., Salman Roghani, R., Fathi, M., Gharooee Ahangar, A., et al. (2021) The comparison effects of intra-articular injection of Platelet Rich Plasma (PRP), Plasma Rich in Growth Factor (PRGF), Hyaluronic Acid (HA), and ozone in knee osteoarthritis; a one year randomized clinical trial. BMC Musculoskelet. Disord., Springer Science and Business Media LLC 22, 134

32 Aslan, S. G., de Sire, A., Köylü, S. U., Tezen, Ö., Atar, M. Ö., Korkmaz, N., et al. (2024) The efficacy of ultrasonography-guided oxygen-ozone therapy versus corticosteroids in patients with knee osteoarthritis: A multicenter randomized controlled trial. J. Back Musculoskelet. Rehabil., IOS Press 37, 1455–1466

33 Fakhari, S., Pishghahi, A., Pourfathi, H., Farzin, H. and Bilehjani, E. (2021) A Comparison Between Low-Level Laser Therapy and Intra-articular Ozone Injection in Knee Osteoarthritis Treatment: A Randomized Clinical Trial: Low-Level Laser or Intra-articular Ozone in Knee Osteoarthritis. J laser Med Sci 12, e44–e44

34 Latini, E., Nusca, S. M., Curci, E. R., Lacopo, A., Di Stasi, V., Santoboni, F., et al. (2025) Ozone and hyaluronic acid, alone and in combination: Exploring temporal dynamics and synergies in intraarticular therapy for knee osteoarthritis. Pain Physician, Pain Physician 28, 347–357

35 Aliyev, D., Akkemik, U. and Asik, I. (2023) Efficacy of an intra-articular ozone injection for chronic knee pain due to osteoarthritis. Altern. Ther. Health Med., Altern Ther Health Med 29, 24–28

36 Sconza, C., Parente, A., Marotta, N., Farì, G., Scaturro, D., Vecchio, M., et al. (2026) Intra-articular injections of oxygen-ozone versus hyaluronic acid for the treatment of knee osteoarthritis: A randomized controlled trial. J. Back Musculoskelet. Rehabil., SAGE Publications 39, 216–227

37 Rahimzadeh, P., Imani, F., Azad Ehyaei, D. and Faiz, S. H. R. (2022) Efficacy of oxygen-ozone therapy and platelet-rich plasma for the treatment of knee osteoarthritis: A meta-analysis and systematic review. Anesth. Pain Med., Brieflands 12, e127121

38 Arias-Vázquez, P. I., Castillo-Avila, R. G., Hernández-Gil, K., Guzzardo, M. N. and Guzzardo, D. R. (2026) Ozone injections reduce pain in knee osteoarthritis: a systematic review and meta-analysis. Med. Gas Res., Ovid Technologies (Wolters Kluwer Health) 16, 286–292

39 Chen, H., Yu, B., Lu, C. and Lin, Q. (2013) The effect of intra-articular injection of different concentrations of ozone on the level of TNF-α, TNF-R1, and TNF-R2 in rats with rheumatoid arthritis. Rheumatol. Int. 33, 1223–1227

40 León Fernández, O. S., Oru, G. T., Viebahn-Hänsler, R., López Cabreja, G., Serrano Espinosa, I. and García Fernández, E. (2022) Medical ozone arrests oxidative damage progression and regulates vasoactive mediator levels in elderly patients (60-70 years) with oxidative etiology diseases. Front. Physiol., Front Physiol 13, 1029805

41 Yao, T.-K., Lee, R.-P., Wu, W.-T., Chen, I.-H., Yu, T.-C. and Yeh, K.-T. (2024) Advances in gouty arthritis management: Integration of established therapies, emerging treatments, and lifestyle interventions. Int. J. Mol. Sci., MDPI AG 25, 10853

42 Haghighat, S. and Oshaghi, S. (2020) Effectiveness of Ozone Injection Therapy in Temporomandibular Disorders. Adv. Biomed. Res. 9, 73

43 Chirumbolo, S., Valdenassi, L., Tirelli, U., Ricevuti, G., Pandolfi, S., Vaiano, F., et al. (2023) The oxygen-ozone adjunct medical treatment according to the protocols from the Italian scientific society of oxygen-ozone therapy: How ozone applications in the blood can influence clinical therapy success via the modulation of cell biology and immunity. Biology (Basel) 12, 1512

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