Objectives To synthesize mechanistic and clinical evidence on oxygen–ozone therapy in musculoskeletal and spinal disorders, and to appraise its safety, dosing patterns, and comparative effectiveness versus standard conservative and interventional care. Design Narrative review of experimental and clinical studies on ozone therapy, integrating mechanistic data with randomized trials, cohort studies, and observational series across peripheral musculoskeletal conditions and spinal disorders, with qualitative synthesis of efficacy, safety, and protocol characteristics. Results Mechanistic data support controlled oxidative preconditioning, Nrf2-mediated antioxidant activation, cytokine modulation, and improved microcirculation, with tissue specific effects on fibroblasts, collagen synthesis, and chondroprotection. Clinically, ozone therapy provides clinically meaningful pain and functional improvements in knee osteoarthritis, tendinopathies, carpal tunnel syndrome, plantar fasciitis, fibromyalgia, piriformis syndrome, and myofascial pain, often comparable to corticosteroids in the short term and potentially synergistic when combined with regenerative or physical modalities. In lumbar disc herniation, intradiscal ozone, alone or combined with steroids or radiofrequency, yields pain and disability outcomes comparable to microdiscectomy in selected patients, with lower complication rates and shorter recovery, although evidence is constrained by heterogeneous dosing, injection techniques, and generally short to mid term follow up, and objective measures such as nerve conduction or imaging change do not always parallel symptomatic gains. Conclusions Ozone therapy appears to be a safe, minimally invasive adjunct or alternative for selected musculoskeletal and spinal disorders, particularly in patients who are poor candidates for surgery or conventional injections. However, substantial protocol heterogeneity and predominance of small, single center studies support the need for large, multicenter randomized trials with standardized dosing, longer term follow up, and cost effectiveness analyses before routine guideline level adoption.
Musculoskeletal and spinal disorders are major global contributors to chronic pain, disability, and loss of productivity. Many patients experience incomplete or temporary improvement with conventional pharmacologic, rehabilitative, or surgical care. This published narrative review in Ozone: Science & Engineering summarizes mechanistic and clinical evidence on oxygen–ozone therapy across peripheral musculoskeletal and spinal conditions, evaluating biological rationale, dosing patterns, comparative effectiveness, safety, and current limitations.
Experimental studies demonstrate that therapeutic ozone, delivered as a controlled oxygen–ozone gas mixture, induces moderate oxidative stress that activates the Nrf2 pathway and upregulates antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. This oxidative preconditioning reduces proinflammatory cytokines such as IL-1 and TNF-α while increasing IL-10, improves microcirculation and tissue oxygenation, and modulates nociceptive pathways. Tissue-specific actions include stimulation of fibroblasts, enhanced collagen synthesis, chondroprotective effects via reduced matrix metalloproteinase activity, and improved cellular metabolism. These mechanisms provide a biological basis for ozone’s application to degenerative and inflammatory musculoskeletal conditions.
Peripheral clinical applications span shoulder disorders, lateral epicondylitis, carpal tunnel syndrome (CTS), knee osteoarthritis (KOA), plantar fasciitis, myofascial pain syndrome, fibromyalgia, and piriformis syndrome. In rotator cuff tendinopathy and calcific tendinitis, randomized trials show that subacromial or peri-tendinous ozone relieves pain and improves function comparably to corticosteroid injections over short-term follow up. For adhesive capsulitis, small randomized and prospective studies report significant improvements in pain and range of motion following intra-articular ozone, with outcomes similar to corticosteroid injections and somewhat less durable than pulsed radiofrequency in one study.
In lateral epicondylitis, evidence includes randomized trials, cross-sectional studies, and retrospective cohorts. While corticosteroids may outperform ozone for some early functional metrics, repeated ozone sessions often provide sustained pain reduction, and retrospective analyses show superior long-term pain outcomes with ozone compared to both corticosteroids and extracorporeal shockwave therapy.
In CTS, several randomized trials demonstrate that ozone injections combined with splinting improve pain and symptom severity more than splinting alone, and produce clinical outcomes similar to corticosteroid injections. However, corticosteroids more consistently improve electrodiagnostic and ultrasound parameters. These findings position ozone as a low-risk, cost-efficient option for mild to moderate CTS when steroids are contraindicated or less desirable.
In KOA, intra-articular ozone provides rapid pain reduction and functional gains, often comparable to hyaluronic acid and approaching platelet-rich plasma (PRP) in early follow up. Long-term outcomes tend to favor PRP and plasma-rich in growth factors, while ozone’s effects may diminish unless repeated or combined with adjunctive modalities. Safety across KOA studies is excellent, with mostly mild transient discomfort. Combination strategies integrating ozone with PRP, low-level laser therapy, corticosteroids, or medications frequently enhance outcomes without new safety concerns.
In plantar fasciitis, randomized trials show that corticosteroids yield quicker early improvement, whereas ozone achieves similar results by three months. PRP tends to outperform ozone in sustained long-term outcomes, but ozone remains a practical option when steroids or biologics are unsuitable.
Systemic ozone applications via autohemotherapy or rectal insufflation have been studied in fibromyalgia, with multiple trials reporting meaningful reductions in pain, fatigue, and sleep disturbances, along with improvements in quality-of-life indices. Adverse effects are generally mild and transient. Myofascial pain syndrome involving localized trigger points also responds effectively to ozone, with results comparable to lidocaine injection and superior to dry needling in one randomized study. In piriformis syndrome, ozone provides substantial short-term relief, although botulinum toxin appears to produce more durable improvements at six months.
Spinal applications primarily involve intradiscal ozone chemonucleolysis for lumbar disc herniation. Across more than 15 clinical studies including over 1,700 patients, intradiscal ozone produces significant reductions in radicular pain and disability, with typical success rates above 70 percent for contained herniations. Long-term follow up up to ten years demonstrates sustained pain reduction in many cases. Comparative studies show that intradiscal ozone achieves outcomes similar to microdiscectomy in selected patients, with advantages of shorter recovery, fewer complications, and lower cost. A non-inferiority randomized trial found that most patients treated with ozone avoided surgery and experienced pain relief comparable to microdiscectomy at six months.
Combination techniques have also been evaluated. Adding percutaneous intradiscal radiofrequency thermocoagulation (PRIFT) to ozone consistently enhances pain relief, disability scores, and patient satisfaction compared with either modality alone. The addition of corticosteroids shows mixed benefit across studies. In comparisons with laser disc decompression (PLDD), intradiscal ozone yields similar pain relief and superior functional outcomes in one randomized trial.
Paravertebral intramuscular ozone injections are effective for acute and chronic low back pain. Randomized controlled data show greater rates of pain-free status and reduced NSAID use compared with sham, despite no corresponding MRI changes. Retrospective data support similar findings.
Across all peripheral and spinal interventions, ozone therapy demonstrates a favorable safety profile, with very low rates of serious complications. Reported adverse events are typically mild, including localized discomfort, transient hypotension, or brief vasovagal symptoms. Severe events such as infection or permanent neurologic deficits are not reported in the reviewed studies.
Despite encouraging results, several limitations temper the strength of evidence. Many studies have small samples, limited blinding, and heterogeneous dosing protocols. Concentrations vary widely (commonly 10–40 µg/mL), injection volumes range from 2 to more than 20 mL, and treatment schedules differ substantially. Follow up frequently emphasizes short-term outcomes, leaving uncertainty regarding long-term structural effects. Objective measures such as nerve conduction, ultrasound, or cartilage imaging often show inconsistent alignment with symptomatic improvements. These factors limit comparability across studies and highlight the need for standardized methodologies.
In summary, this published narrative review indicates that ozone therapy is a promising, safe, and minimally invasive treatment for selected musculoskeletal and spinal disorders. It may serve as an effective adjunct or alternative for patients who do not respond adequately to standard care or are poor candidates for surgery. Nevertheless, widespread adoption requires large, multicenter randomized trials with standardized dosing, longer follow up, and inclusion of both subjective and objective outcomes.
