Ozone Therapy For Pain

At a glance:

1. Pain is biopsychosocial. It’s complex, difficult to diagnose, and difficult to treat. Radiology doesn’t always see pain and chronic pain can come from the brain rather than the actual damage itself.
2. Musculoskeletal issues are the one category where there is robust evidence supporting the safety and effectiveness of ozone therapy, particularly ozone injections. There is, however, less evidence for other methods such as topical ozone oil and systemic ozone therapies. 
3. Aside from stimulating Nrf2, ozone therapy may help with pain by mitigating the cell danger response, breaking down inflammatory molecules that signal pain, reducing pain neuron signaling, and supporting the production of molecules that help resolve inflammation.
4. Beyond reducing pain, ozone therapy also supports tissue regeneration and overall healing functions in the area treated with ozone. In many cases, it can accelerate overall healing from musculoskeletal injuries.

What is pain and why is it so hard to measure and treat?

Whether it’s sharp, achy, dull, or lingering, pain is a complex and multifaceted experience that serves as the body’s natural alarm system, signaling potential harm or injury. Pain can be caused by a wide range of factors, including injury, illness, and inflammation. 

Pain is not just physical–it is also biopsychosocial. Much of the pain perception comes from the brain [1]. There are numerous paradoxes in pain research and how we experience pain. It’s totally possible to be severely injured while running away from danger and not feel any pain until you’re safe from the danger. Also, not all patients who sustain injuries develop chronic pain, and pain researchers are still trying to understand why [2]. 

Just like any perplexing and paradoxical chronic conditions, mainstream medicine struggles to treat and diagnose pain, leaving many patients suffering. 

There are two types of pain: acute and chronic. 

Acute pain

Acute pain is the body’s immediate response to an injury or a specific harmful stimulus. It is typically short-lived, lasting from a few seconds to several weeks, and usually subsides as the underlying cause is treated or heals. 

Acute pain is often described as sharp or intense, and its primary function is protective—it prompts individuals to withdraw from damaging situations and seek care. Examples include pain from cuts, burns, surgery, or any type of acute inflammation. 

Despite its intensity, acute pain is generally temporary and, with appropriate intervention, can be effectively managed and resolved.

Chronic pain

Chronic pain is a persistent and often debilitating condition that lasts for weeks, months, or even years beyond the initial cause or injury. 

Unlike acute pain, which serves as a direct response to tissue damage, chronic pain can occur even after the original injury has healed or in the absence of a clear physical cause. It can arise from conditions such as arthritis, nerve damage, and ongoing inflammation.

Chronic pain can significantly impact a person’s daily life, through:

• Limiting mobility
• Disrupting sleep
• Reducing overall quality of life

It can also lead to or be worsened by mental health issues such as anxiety or depression.

Because of its complex nature, chronic pain requires a multifaceted approach to management, often involving a personalized combination of:

• Medication(s) or other pain management modalities like massages and ozone therapy
• Physical therapy and exercise
• Lifestyle adjustments
• Addressing psychology and the nervous system, such as psychotherapy and brain rewiring modalities like pain reprocessing therapy [3]

How does ozone therapy help with pain and inflammation?

Like other complex conditions, Cell Danger Response, mitochondrial dysfunction, oxidative stress, and low oxygen are major contributors to pain, both chronic and acute. Inflammation also tends to be a major contributor. 

For acute pain, inflammation can arise from the damaged tissue and the immune responses to the damage. Whereas, for chronic pain, mitochondrial dysfunction could also involve pain neurons, signaling pathways, and the brain [4]. 

Many interventions that boost mitochondrial function, reduce inflammation, or improve blood flow can help relieve pain, especially chronic pain or injuries that don’t heal well. These interventions include low-level laser therapy, massages, transcutaneous electrical nerve stimulation, hyperbaric oxygen therapy, and exercise. Given that ozone therapy addresses these similar mechanisms, it’s a powerful adjunctive treatment that can provide relief. In addition, ozone therapy stimulates several regenerative pathways, so it also stimulates actual healing beyond just relief. 

Addressing the Cell Danger Response

Pain represents danger perception that causes you to get yourself out of harm’s way, so it makes sense that things that cause injury invoke the Cell Danger Response. Then, cases that become chronic pain happen because the CDR cannot resolve. This could be due to pre-existing toxicity, traumas, or the brain rewiring to anticipate danger. While this theory hasn’t been completely proven, many studies have demonstrated that purines outside the cells, a key feature of CDR, helps coordinate chronic pain outside of the pain neurons [5].

During CDR, the mitochondria dial down their functions and oxygen consumption. At the same time, inflammation can reduce blood flow and oxygen supply to the area, compromising mitochondrial function. Altogether, these lead to reduced energy production, increased oxidative stress, and slowed healing processes.

Ozone therapy may help with pain by reviving mitochondrial function and jumpstarting the resolution of this CDR. When administered, ozone interacts with biological tissues, leading to the formation of ozonides and other reactive oxygen species (ROS) which stimulate Nrf2 and other downstream processes. These ROS play a vital role in signaling pathways that promote mitochondrial activity [6]. At the same time, systemic ozone therapy and ozone-oxygen injections enhance tissue oxygenation and increase oxygen availability at the cellular level [7, 8].

The antioxidant pathway activation and oxygen stimulate the production of ATP for use inside the cells, improving cellular metabolism and reducing the accumulation of pro-inflammatory substances [9].

By enhancing mitochondrial function, ozone therapy not only aids in the repair of damaged tissues but also helps to modulate pain perception. Improved tissue oxygenation and mitochondrial activity can lead to faster healing, less inflammation, and thus less pain. 

This mechanism makes ozone therapy particularly effective in treating conditions where chronic inflammation and low oxygen play a central role.

Stimulating Nrf2 and inhibiting Nf-kB

Nrf2 is your cellular project manager that helps manage antioxidant responses.

By stimulating the Nrf2 pathway, ozone therapy enhances the body’s natural antioxidant response, helping to counteract oxidative stress and inflammation, which contribute to pain severity and slow healing [10].

Nrf2 suppresses NF-κB, your cell’s primary coordinator of inflammation and immune response. NF-κB coordinates cellular production of cytokines and inflammatory enzymes in response to infections and injuries. However, chronic activation of the NF-κB pathway is associated with persistent inflammation and pain [11].

By balancing these two pathways—upregulating Nrf2 and downregulating NF-κB—ozone therapy effectively reduces inflammation and oxidative stress, addressing the underlying mechanisms that contribute to both acute and chronic pain [12].

Breaking down inflammatory mediators and pain molecules

Ozone therapy can also help break down inflammatory mediators, such as cytokines, prostaglandins, bradykinin, and other inflammatory substances [13].

While necessary for healing, these mediators can contribute to chronic inflammation and pain when produced in excess. Ozone helps break down arachidonic acid, a fatty acid that is a precursor to various inflammatory prostaglandins [6]. By modulating this pathway, ozone reduces the production of pro-inflammatory substances that exacerbate pain and swelling. 

Additionally, the therapy can disrupt the activity of enzymes and other molecules involved in sustaining inflammation, thereby alleviating symptoms more effectively. 

Producing molecules that help resolve inflammation

Oxidized fatty acids, also known as oxylipins, play a critical role in the resolution of inflammation. This is important in preventing chronic inflammation and promoting tissue healing. These molecules are derived from the oxidation of polyunsaturated fatty acids (PUFAs) and have been found to have potent anti-inflammatory properties [14, 15]. However, lack of oxygen in the tissue can prevent enough of these molecules from forming.

Ozone therapy creates oxidized fatty acids and increases the oxidative load in the body. This may increase oxylipins, which oxidized fats that help resolve inflammatory responses [16].

These oxylipins can promote the clearance of inflammatory cells from the site of injury and stimulate the production of pro-resolving mediators, such as resolvins and protectins. These mediators play a vital role in shutting down the inflammatory process and initiating the healing phase [17].

Working on the nociceptors (pain neurons)

Nociceptors are sensory neurons specialized for detecting painful stimuli and sending pain signals to the brain [18]. In conditions of chronic pain, nociceptors can become sensitized, resulting in an exaggerated response to pain stimuli or even pain in response to non-painful stimuli [19].

Ozone therapy reduces nociceptor sensitivity and, consequently, the perception of pain. 

When ozone is introduced into the body, it can alter the environment around nociceptors by reducing local inflammation, oxidative stress, and Cell Danger Response. This reduction in inflammation helps to decrease the activation of nociceptors, lowering the intensity of pain signals sent to the brain [20].

Ozone therapy also promotes the release of your own opioids and other pain-relieving molecules, whether in the brain or near the injury sites. These molecules can bind to receptors on nociceptors and inhibit their activity [21].

This dual action makes ozone therapy an effective pain management approach, particularly in cases where traditional pain management strategies have been insufficient.

Stimulating growth factors

Unlike other treatments for pain and injuries, ozone therapy can stimulate growth factors, which can encourage regenerative processes to heal the damage.

Ozone exposure temporarily increases IL-8, which attracts immune cells to come and help eliminate cellular debris. It can also increase growth factors in the immediate areas, such as platelet–derived growth factor and transforming growth factors [22]. 

Routes of Ozone-Oxygen Administration for Pain

Local injection of gas or saline into the joints or muscles

One of the most direct methods of administering ozone therapy for pain relief is the local injection of ozone gas into affected joints or muscles [23]. This provides targeted pain relief and promotes healing.

This approach allows the ozone to act directly on the site of pain to create a small amount of oxidative stress that jumpstarts the healing. At concentrations 20 - 40 μg/mL, it reduces inflammation, increases tissue oxygenation, and modulates nociceptor activity. Whereas, at higher concentrations, it may increase inflammation which may help fight infections [6].  

Ozone injection or prolozone is particularly effective for conditions such as:

• Arthritis
• Tendonitis
• Musculoskeletal disorders

Ozone oil massage

Ozone oil massage involves the topical application of ozonated oil, which is oil infused with ozone, directly onto the skin over areas experiencing pain or inflammation [24]. It delivers fat-based molecules that ozone exposure creates. These molecules can penetrate the skin and deliver its anti-inflammatory and analgesic effects locally. 

Ozone oil massage is particularly useful for treating surface-level pain conditions, such as:

• Muscle soreness
• Minor joint pain
• Skin-related inflammatory issues

Although this method has the least evidence for it, there is one triple-blind clinical trial in 80 severe osteoarthritis patients over 50 years old. The patients were instructed to apply 0.5 mL of oils topically on the affected joints and massage until complete absorption twice daily for 60 days. 37 patients received ozone oil massage while 43 received the placebo. The ozone oil group experienced statistically significant pain relief [25]. 

Systemic ozone treatment

Systemic ozone treatment involves administering ozone throughout the body to address widespread pain and inflammation. Two common methods are autohemotherapy and rectal insufflation. 

Both methods are used to:

• Reduce systemic inflammation
• Boost immune function
• Improve overall oxygenation, including to the brain
• Improve overall sense of wellbeing

These benefits make them effective for conditions characterized by chronic pain and widespread inflammation.

How Effective is Ozone Therapy for Musculoskeletal Disorders and Chronic Pain?

According to a July 2024 systematic review [26], this is a summary of evidence levels for musculoskeletal disorders based on the Oxford Centre for Evidence-Based Medicine Hierarchy:

‍

Level II = Randomized controlled trials and systematic reviews with meta-analyses

Level III = non-randomized or uncontrolled trials and case controlled studies

Level IV = Solidarity study or systematic review of preclinical therapies

There’s never been a more dire need for effective pain management and injuries rehab. For many desperate patients, ozone therapy is very promising. We need to keep in mind that pain and injuries, especially chronic, tend to be complex and involve many contributing factors. After all, pain involves biological, psychological, and social factors.

Ozone therapy is not on its own a cure, but it can be part of a holistic pain management and injury recovery program (which are both beyond the scope of this book). While certain ozone treatments can be done at home, the best studied method of ozone therapy for musculoskeletal issues is joint injections. Therefore, you want to find a holistic doctor who can help guide a treatment plan—one of whom is Dr. George Kramer, a pain remedy and pain management specialist.

Dr. Kramer has a clinic in Minneapolis-St.Paul, Minnesota, where he treats many patients with back pain and various musculoskeletal disorders. He describes the history of his own practice as “alternative medicine in musculoskeletal before there was such a thing,” and his methods have included hot and cold temperature therapies, acupuncture, dietary supplements, lifestyle changes and many other interventions. Over the course of 30 years, Dr. Kramer has treated tens of thousands patients through his practice.

Most specifically, Dr. Kramer’s practice has been known for using prolotherapy—the use of injected prolozone into joints and ligaments—to treat patients with chronic pain and musculoskeletal issues. His practice has shown that patients can often avoid invasive joint surgeries by doing prolotherapy, specifically one woman from Michigan:

She was scheduled for carpal tunnel surgeries and cubital tunnel, where the nerve damage pinches your elbow. She was scheduled for four surgeries . . . and I treated with prolozone once, maybe twice. I saw her three years later for her knee and I said, “What happened to your wrist and elbows?” She said “I was fine!” So she didn’t need four surgeries because of prolozone . . . it’s the strongest tool for healing that I’ve found.

While Dr. Kramer treats all kinds of local and chronic pain using prolozone and other therapies, other medical research and case studies exist showing that ozone therapy in various forms can support specific and individual musculoskeletal issues as well.

Dr. Dan Kellams of Peak Vitality who runs a clinic in Golden Colorado and Houston says:

We treat a lot of neuropathy and joint issues in our office. We do acupuncture, functional medicine, umbilical cord tissues, and PRP, but we’ve never seen the results we see with ozone. It’s amazing. It’s the fastest turnaround we’ve ever seen. Now, we don’t even talk about doing anything else with people. Ozone is the most consistent regenerative type of therapy that we see beyond anything else. We recommended it to a few other doctors.

Case Studies and Research on Ozone Therapy for Musculoskeletal Disorders

Degenerative Disc Disease 

In a case series published in Acta Neurochirurgica, Dr. Matteo Bonetti and his team of physicians used oxygen-ozone therapy for degenerative spine disease in elderly patients. Between April 2004 and March 2008, their team chose 129 patients who showed evidence of spondyloarthrosis and disc degeneration and who had contraindications preventing them from taking standard anti-inflammatory and analgesic drugs.

The treatment was CT-guided injections of 10 cc of ozone-oxygen gas mix at 25 µg/mL into each infiltration point.

At 3 months:

• 57.3% (74) of patients had near complete disappearance of low back pain
• 24.8% (32) were satisfied with the treatment but only had partial reduction of pain
• 17.9% (23) had little to no benefit

At 1 year follow up, 2 patients had passed. However, 33.9% (43/127) patients still had a clear-cut improvement in quality of life as their pain had resolved and they were able to return to daily activities. Ten of these patients no longer required walking aids. The pain came back for 34 patients with partial resolution of pain, but the recurred pain was much milder than before the ozone-oxygen treatment. Only 1 patient in this study chose surgical decompression. 

The author speculated that the ozone delivered its benefits through normalizing cytokines, prostaglandins, and oxidative stress, while increasing circulation into the area. The effects can wear off over time, however, if the structural issues causing the pain are not resolved. The patients whose pain resisted the treatment were those who had bony structures that continued to irritate the nociceptors. Of the 34 patients with satisfactory outcomes, 29 requested another cycle of ozone treatment. For those 50 who didn’t receive benefits, 22 requested a new cycle of treatment. 

The study concluded that ozone therapy was an ideal treatment with no side effects in elderly patients with degenerative spine disease [27].

Herniated Discs

Herniated discs are a common injury for athletes and there’s an increased risk of them occurring  with age. The condition occurs when a tear in the fibrous ring of an intervertebral disc allows the central portion to bulge out, leading to significant pain, discomfort, and hindered mobility. There are few treatment options other than pain management, physical therapy, and surgery. Fortunately, ozone therapy is a very safe, effective, and minimally invasive option.

Ozone-oxygen injections for lumbar disc herniations have been very well-studied, including many clinical trials that are double-blinded and even a few meta-analyses. A 2010 meta-analysis analyzed 12 studies and almost 8,000 patients. On average, the pain went down by 3.9 points out of 10 and Oswestry disability index improved by 25.7. The likelihood of improvement was 79.7%. The likelihood of complications was 0.064% and recovery time was significantly shorter [28]. 

A 2024 meta-analysis evaluated the effectiveness of ozone injections for lumbar disc herniations. It reported that at ≥ 6 months, the therapeutic was 3.95 times more likely to give superior outcome to steroid injections or conventional medications.

• < 6 months the reduction in VAS after injection was 2.53 points higher than after steroid injections. 
• At 6 months, change in VAS was 1.65 points
• At 12 months, 1.52 points

This meta-analysis concluded that ozone injections were more effective than steroids and other oral medications [29]. 

Ozone-oxygen can work as a chemonucleolysis agent that helps to break down protruded disc tissue. After ozone-oxygen gas injection, the ozone oxidizes the proteoglycan inside the nuclear pulposus, causing it to denature and shrink, releasing water. The matrix is then replaced by fibrous tissues and new cells in about 5 weeks. This disk shrinkage reduces nerve root compression, while increasing local circulation, tissue oxygenation, analgesic, and anti-inflammatory actions. Overall, the ozone-oxygen injection is less invasive and less traumatic than other invasive treatments for herniation [30]. Unlike enzymatic chemonucleolysis, ozone-oxygen doesn’t cause allergies or other adverse immune responses.

An Italian study enrolled 104 patients for ozone injection in between vertebral discs. Subsequently, they followed the patients for 18 months with the visual analog scale (VAS, from 1 to 10), Japanese Orthopedic Association (JOA) scale, and Overall Patient Rating Scale (OPRS). The study also followed up on the structural changes of the herniation after 5 months with MRI or CT scans. 

On average, the pain levels improved by 3.77 out of 10 on the VAS scale. JOA improved by 54.7% and OPRS improved by 71.55%. With respect to imaging, 37% of patients had complete disappearance of the herniation, while 41% had a reduction in volume, and 22% had unchanged herniation [31]. 

The rare reported cases of complications were due to infections at the injection site, which can also happen from steroid and other injections into the spine [32, 33]. While the clinical evidence has been very positive for ozone injections for lumbar disc herniation, the effects may be individual. In some cases, it can completely resolve the herniation. In others, it complements pharmacological, physiatric, or surgical treatments. 

Sciatica

Since many musculoskeletal issues that originate or branch off of the spine work in similar ways (such as inflammation or muscle and tissue tears creating pinched nerves and nerve pain), ozone therapy provides similar benefits for many of them, including sciatica and lower back pain more generally.

In a study published in La Radiologica Medica, researchers treated more than 1000 patients with intradiscal ozone for lower lumbar and sciatic pain while they were under anesthesia between September 1995 and April 1997. Of those patients, researchers selected 50 for these treatments at intervals of three, 15, and 30 days, with follow-ups after each one and a final follow-up three months later.

The study’s results showed 68% positive results, meaning those patients didn’t need surgery or other medical and/or pharmaceutical care. In the conclusion of their study, the care team were optimistic about the use of ozone therapy as an early intervention for sciatica and back pain:

Ozone therapy, thanks to its ease of execution and noninvasiveness, permits the successful outpatient treatment of lumbar sciatic pain. Moreover, the lack of major complications and the good results obtained compared to other methods, such as chemonucleolysis, percutaneous automated discectomy, microsurgery and conventional surgery, suggest that ozone therapy can be considered the treatment of choice for lumbar sciatic pain and a valid alternative to surgery in many cases [34].

Steroid treatment is another common and intermediate treatment method for sciatica, though using steroids alone is not always entirely effective. Still, one case study examined the use of ozone therapy in addition to steroid treatment and showed enhanced results.

The study compared 150 patients—86 men and 73 women between the ages of 18 to 71—who were split into two groups, one of which received injected steroids (77 patients) and another which did the same with the addition of ozone therapy (82 patients). After six months, results showed that 47% of patients in the steroid-only group had a successful course of treatment as compared to a 74% success rate in the group of steroids and ozone [35].

Tendonitis 

Tendonitis can affect many different joints in the body, and most cases tend to come from excess physical strain on a certain part of the body. Tendons and ligaments tend to heal very slowly as they naturally have low blood supply. Also, autoimmune issues, mold toxicity, and other musculoskeletal issues can also cause or exacerbate these problems. 

A rabbit study compared 28 rabbits divided into 4 groups:

‍
1. R - Rotator cuff repair

2. RP - Rotator cuff repair with platelet-rich plasma (PRP)

3. RO - Rotator cuff repair + ozone

4. RPO - Rotator cuff repair + PRP + ozone

The study found that the RO group had a significant increase in collagen fibers and their organization, although mechanical strengths were not significantly better than the R group. This is possibly because the tendon healing hadn’t caught up in terms of strength. Whereas, PRP activated growth factors to a greater extent. The RPO group had the greatest tissue and strength improvements [36]. You’re not a rabbit and they’d need a clinical study to confirm the results in humans, but it shows that ozone therapy may be beneficial combined with another therapy like PRP injections.

A clinical study looked at rotator cuff injuries in 40 patients, 26 men and 14 women, who had been experiencing shoulder pain for approximately six months. According to the researchers, “ultrasound-guided infiltration of oxygen-O3 therapy proved to be an effective treatment method in partial tears of the supraspinatus tendon” [30].

Carpal Tunnel Syndrome

A case study by Zambello et al. showed that 90% of carpal tunnel patients had “significant improvement” after getting injections of ozone therapy. After a year, 17% noted that they had good control over their symptoms and 70% noted that they no longer experienced any symptoms [37]. 

Another randomized controlled trial corroborated this result by comparing carpal tunnel patients treated with ozone injections vs. methylprednisolone, a common steroid treatment.

Group O received ozone/oxygen injections, and Group M received methylprednisolone acetate and lidocaine injections. The study evaluated pain levels using the Visual Analog Scale (VAS), hand functional status with the Cochin Hand Function Scale (CHFS), and median nerve function through electrophysiologic studies at baseline, 1 week, 1 month, 3 months, and 6 months post-injection.

The results indicated that Group M showed significant  (p < 0.05):

• Reduction in VAS at 1 week, 3 months, and 6 months. 
• Reduction in CHFS scores after 6 months, indicating improved hand function. 
• Improved sensory conduction and motor distal latency at 3 and 6 months.

The study concluded that ozone therapy provided more significant long-term pain relief, improved hand function, and enhanced median nerve conduction over six months than steroids [38].

Fibromyalgia

A randomized controlled trial aimed to evaluate the effectiveness of ozone therapy (OT) as an additional treatment for fibromyalgia (FM), a chronic condition characterized by widespread pain, fatigue, and sleep disturbances [39]. 

54 patients were divided into an OT group and a placebo control (PC) group. Participants received ozone therapy or placebo in the form of major autohemotherapy (MaAHT) and minor autohemotherapy (MiAHT) twice a week for a total of 10 sessions. 

The treatment’s effectiveness was assessed using the Fibromyalgia Impact Questionnaire (FIQ), Pittsburgh Sleep Quality Index (PSQI), and 12-item Short-Form Health Survey (SF-12) before and after the intervention.

The results showed that the OT group experienced significant (p < 0.05):

• Improvements in specific FIQ subscales, such as feeling good and fatigue 
• PSQI total score and subscales, including subjective sleep quality, sleep latency, and sleep disturbances.

Ozone therapy, particularly when applied via autohemotherapy, can improve specific aspects of fibromyalgia symptoms and sleep quality during the treatment period.

Peripheral neuropathy

There are numerous causes of neuropathy, from metabolic issues to infections, autoimmune disease, toxic exposures, metabolic issues, hormone imbalances, genetics, physical traumas, and more. Ozone therapy may be more effective for certain causes of neuropathy than others.

An RCT evaluated the efficacy of combining pulsed radiofrequency therapy with ozone injection for treating acute herpes zoster neuralgia (shingles pain) in 164 middle-aged and elderly adults [40]. 

The treatments’ effectiveness was assessed using Numeric Rating Scale (NRS) scores. The incidence of clinically significant prolonged nerve pain after the shingles had resolved and any complications were also recorded.

Results demonstrated significant (p < 0.05):

• Reductions in NRS scores and gabapentin doses post-treatment compared to baseline
• Lower doses of gabapentin postoperatively 
• Reduction in prolonged nerve pain incidences at 4, 12, and 24 weeks post-treatment

No adverse reactions were reported in either group.

Combination therapy provides longer-lasting pain relief, reduces the incidence of PHN, lowers the need for medication, and improves the quality of life.

An animal study explored the effects of ozone preconditioning on preventing cisplatin (a chemotherapy drug) induced nephrotoxicity. Rats were preconditioned with ozone via rectal insufflation at various concentrations (10, 20, 30, 50, or 70 µg/mL) for 15 consecutive days before receiving an intraperitoneal injection of cisplatin, a chemotherapy drug known for causing kidney damage [41].

Cisplatin significantly increased serum creatinine levels (a marker of kidney damage) and free radicals, while reducing antioxidant levels in the kidneys. 

High concentrations of ozone (50 and 70 µg/mL) administered with cisplatin did not improve these outcomes and even worsened some measures. 

However, moderate concentrations of ozone (20 and 30 µg/mL) administered before cisplatin reduced the rise in creatinine levels and oxidative stress, and preserved antioxidant levels. 

Histopathological analysis revealed that cisplatin alone caused severe kidney damage, while rats preconditioned with 30 µg/mL of ozone showed kidney tissue similar to that of untreated rats, with minimal damage.

Complex Regional Pain Syndrome

A case report discussed the potential of ozone therapy as a novel approach for treating pain, specifically focusing on Complex Regional Pain Syndrome (CRPS), also known as Reflex Sympathetic Dystrophy (RSD) [42]. 

CRPS is a multifaceted and painful disorder that is difficult to manage with conventional treatments. The report highlights ozone therapy's unique mechanisms of action, which include oxygenation, immune modulation, anti-infective, and anti-inflammatory. All of these may address the underlying factors contributing to CRPS and other chronic pain conditions.

The case presented involves an 11-year-old girl diagnosed with CRPS and frequent pseudoseizures, who had not responded to traditional pain management, including opioids. She was treated with direct intravenous ozone therapy nearly daily, resulting in rapid improvement. After 120 sessions, all symptoms of CRPS and pseudoseizures had disappeared. 

While direct intravenous ozone therapy is not a safe form of administration, alternatives that may be more effective include major autohemotherapy. This report suggests that systemic ozone therapy may offer a safe, effective, and relatively inexpensive treatment option for chronic pain conditions like CRPS, especially when conventional treatments fail. 

The authors advocate for further institutional studies on ozone therapy, despite its lack of patentability and financial incentive.

Knee Osteoarthritis

According to a 2024 umbrella review of systematic reviews, thAn RCT evaluated the therapeutic effects of combining ozone with articular injection of sodium hyaluronate on 292 patients with knee osteoarthritis (KOA) to assess changes in their inflammatory factors and hemorheological indices [43]. 

The ozone group (n=146) received ozone therapy combined with sodium hyaluronate injections. The control group (n=146) was treated with oral glucosamine hydrochloride tablets and sodium hyaluronate injections. The treatment was administered once a week for five consecutive weeks.

The results showed that the ozone group experienced significantly (p < 0.05): 

• Lower Visual Analogue Scale (VAS) scores for pain
• Higher knee function based on the Hospital for Special Surgery (HSS) knee scores  
• Total response rate to treatment
• Lower levels of inflammatory factors in the joint fluid 
• Improved blood indicesere have been 15 randomized controlled trials in 6 countries that evaluated the safety and effectiveness of ozone injections for knee osteoarthritis. Three of these trials reported that ozone injections provided better pain reduction than placebo, but may not be superior to other treatments [44]. 

The study concludes that ozone combined with articular injection of sodium hyaluronate offers significant therapeutic benefits for patients with KOA, providing:

• Better pain relief
• Improved knee function
• A reduction in inflammatory factors

Conclusion

Like other chronic illnesses, musculoskeletal issues are often not well understood and can make life nearly unmanageable for the people suffering from them. Additionally, many of the medications and treatment available for these diseases only treat surface-level symptoms, or treat pain at the expense of the patient’s health (and with an additional risk of addiction in some cases).

Though ozone therapy is not a cure for these diseases, ongoing research shows that it may help provide relief and often resolve the issues. Most importantly, it serves as an intermediary treatment option between very invasive treatment options like surgery and more surface-level options like physical therapy for those who need it the most. For several conditions like lumbar back herniations and osteoarthritis, there is ample evidence confirming the safety and effectiveness of ozone therapy.