Oxygen–Ozone Therapy in the Rehabilitation Field State of the Art on Mechanisms of Action, Safety and Effectiveness in Patients with Musculoskeletal Disorders

Background

Musculoskeletal disorders such as chronic low back pain and knee osteoarthritis are a major cause of disability and healthcare spending worldwide. Conventional management options, including analgesics, physical therapy and, eventually, surgery, do not suit every patient, and researchers have continued to look for conservative, minimally invasive alternatives. Oxygen-ozone (O2O3) therapy - the injection of a controlled mixture of medical oxygen and ozone - has been used clinically for decades in this context, but the authors note that its underlying biochemical effects have still not been fully mapped out, even though its chemical properties suggest plausible therapeutic pathways worth reviewing in detail.

Study design

This is a narrative literature review, not a systematic review or clinical trial. A multidisciplinary group of Italian rehabilitation medicine researchers examined and synthesised existing published research - including mechanistic laboratory work and clinical studies - on O2O3 therapy for musculoskeletal conditions, with particular focus on low back pain and knee osteoarthritis. The review draws together proposed biological mechanisms of action alongside the available clinical evidence on effectiveness and safety, rather than applying a predefined systematic search protocol or statistical pooling of results.

Findings

The authors describe several proposed mechanisms by which O2O3 may act. Mild, controlled oxidative stress appears to activate the Nrf2 signalling pathway, which switches on the body's own antioxidant defences. Ozone is also described as influencing prostaglandin synthesis, which may reduce inflammatory mediators such as IL-6, IL-8 and TNF-alpha. In the spine, ozone is proposed to chemically alter glycosaminoglycan chains within the intervertebral disc, reducing water content and hernia volume, while increases in nitric oxide and prostaglandins may improve local blood flow and raised serotonin and endogenous opioids may contribute to pain relief.

On the clinical evidence reviewed, intramuscular-paravertebral O2O3 injections were associated with pain reduction and improved function in patients with low back pain across the studies cited, with reported success rates in the region of 70-80% for pain reduction, and one cited study found a specific concentration (40 micrograms/mL) more effective than a higher one (60 micrograms/mL), which was linked to increased inflammatory markers rather than benefit. For knee osteoarthritis, intra-articular O2O3 injections were reported as superior to placebo for pain and mobility in the studies reviewed, and broadly comparable to hyaluronic acid injections in the short-to-medium term (three to six months), though some studies found hyaluronic acid slightly more effective at later follow-up.

What the authors concluded

The review authors concluded that O2O3 therapy appears to reduce pain and improve functioning in patients with low back pain and knee osteoarthritis, and that it represents a generally safe and effective conservative or adjuvant option in musculoskeletal rehabilitation. They stated that further research is warranted to clarify its therapeutic effects on other musculoskeletal conditions, and called for standardised medical guidelines covering indications, dosing and administration technique.

Limitations of this study

As a narrative review rather than a systematic review, this paper does not apply a formal, reproducible search strategy or statistical synthesis, and the authors' selection and interpretation of the underlying studies could introduce bias. The authors themselves note that the primary studies reviewed varied widely in treatment protocols, concentrations and administration methods, that many were of lower methodological quality, and that no standardised clinical guidelines currently exist for O2O3 use. For low back pain in particular, the high rate of spontaneous natural regression of disc herniation (reported as up to 90% in some cases) makes it difficult to separate treatment effect from natural resolution. The authors also note that adverse events - including vagal reactions, injection-site pain or haematoma, local infection and, rarely, more serious complications - are generally linked to incorrect administration technique rather than the therapy itself, and that certain patients (for example those with glucose-6-phosphate dehydrogenase deficiency, uncontrolled hyperthyroidism or severe cardiovascular disease) should not receive it.