The use of Ozone in Chronic Joint Pain
Ross Hauser, MD
The Use of Ozone in Chronic Joint Pain
There is a significant amount of research surrounding the use of ozone (O3) in treating various diseases and illnesses. In this article, we will present some of the research presenting various outcomes in the use of ozone gas for problems of chronic pain from osteoarthritis and degenerative joint and disc disease.
Early on in our practice, in the mid-1990s, we started to get questions about ozone as a pain treatment. Ozone gas injections had already been utilized for decades as a wound treatment but interest had started to peak again in the late 1980s and early 1990s. A 1989 study from the University of Bologna in Italy (1) examined the effects of an oxygen-ozone mixture (called medical ozone) injected into patients with knee osteoarthritis.
- 156 patients were treated and divided into 3 groups:
- Those with post-traumatic knee disorders,
- those with arthritis without marked bone deformities (bone spurring) and
- those arthritis with marked bone deformities.
- In the first two groups, optimal or good results were obtained using ozone. Good results include less pain, and better function. In the third group, the more severe knee osteoarthritis group, the ozone did not provide enough benefit to help the patient’s situation, and other therapies were then added to stop the advancing degenerative process. In conclusion, the researchers noted, that knee joint disorders can very successfully be treated by means of an oxygen-ozone mixture locally administered in developing but perhaps not advanced osteoarthritis.
Research like this led the way for more research into ozone therapy. Let’s look at the last 25 years of research and clinical observations.
The concept behind how ozone-oxygen therapy works.
As mentioned, ozone is a gas and its anti-inflammatory and wound-healing benefits in certain cases have been documented throughout medical research. A 2011 review published in the journal Journal of Natural Science, Biology, and Medicine (2) described ozone’s effects as “proven, consistent, safe and with minimal and preventable side effects” in the use of disinfecting and sterilizing, and in the treatment of certain diseases. Mechanism of actions (it works by) is by inactivation of bacteria, viruses, fungi, yeast and protozoa, stimulation of oxygen metabolism, activation of the immune system.” Most commonly, “Diseases treated are infected wounds, circulatory disorders, geriatric conditions, macular degeneration, viral diseases, rheumatism/arthritis, cancer, SARS and AIDS.”
In March 2021, in the journal Biomolecules (3) medical university researchers in Italy gave a broad outline of how ozone-oxygen therapy helps patients with joint pain. Here is what they wrote:
“Several studies have assessed the effects of O2-O3 (Oxygen-Ozone) therapy in different pathological conditions related to musculoskeletal pain. It is widely accepted that pain is a common symptom related to the inflammation process, and Oxygen-Ozone therapy might play a key role not only in the management of inflammation but also in nociceptive perception (the production or reduction of nerve/pain messages) and modulation . . . (There is stimulation or) an increase in serotonin and endogenous opioids (production, the body’s natural painkiller response, which) has been shown after Oxygen-Ozone administration, and these antioxidant molecules could induce pain relief by stimulating antinociceptive pathways (simply the body’s inflammatory response).
Hypoxia (low oxygen levels) and vascularization (blood vessel blockage or disease) impairment are common pathological features in muscle wasting and musculoskeletal disorders; thus the potential role of Oxygen-Ozone therapy in hypoxic tissues may be related to increased production of nitric oxide, adenosine, and prostaglandins, with a resulting positive role in the vasodilatation process.
Taken together, all these findings suggested that oxygen-ozone therapy might exert its positive effects in several tissues due to the moderate oxidative stress produced by ozone interactions with biological components. However, it should be noted that “the thin red line” between O3’s beneficial effects and toxicity could be related to the strength of the oxidative stress.”
In summary: Oxygen-Ozone therapy can work as
- Circulation enhancer
- Tissue repair mechanism.
Ozone and joint damaging chronic oxidative stress
In June 2021 in the orthopedic journal EFORT Open Reviews (4) researchers examined the anti-oxidative stress aspects of intra-articular ozone injections. They explain:
“The rationale behind the use of intra-articular ozone (O3) therapy arose from the assumption that chronic oxidative stress plays an important role in osteoarthritis. . . Clinical experiences and research have considered ozone gas as a powerful anti-inflammatory, immune-modulatory substance. Due to its high reactivity, it may be able to reduce oxidative stress, stimulate fibroblastic joint repair, and may promote new cartilage growth.”
Ozone gas in musculoskeletal disorders
A detailed and precise analysis of ozone gas and musculoskeletal disorders is presented in the journal Medical Gas Research, September 2018. (5) Here researchers examined the role of ozone in a myriad of disorders including lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder. Here are some learning points from that research:
Effectiveness in temporomandibular joint disorder
From the September 2018 research: The researchers found that the use of ozone therapy has been much more effective than medication therapy in patients with temporomandibular joint disorder and high pain scores. Ozone can relieve pain and increase the maximum voluntary interincisal mouth opening values. The researchers speculated that ozone gas promotes new cartilage growth as well as reduces inflammation.
Updated research: In a separate study Italian researchers writing in the International Journal of Molecular Sciences (6) published a February 2022 comprehensive review aimed at investigating the effects of O2O3 ozone therapy on pro-inflammatory cytokines serum levels (inflammation) as a modulator of oxidative stress (working as an anti-inflammatory) in patients with musculoskeletal and temporomandibular disorders. Ozone therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune overactivation. This study suggests that ozone therapy might reduce serum levels of interleukin 6 in patients with TMD, low back pain, knee osteoarthritis, and rheumatic diseases with a concrete and measurable interaction with the inflammatory pathway. However, to date, further studies are needed to clarify the effects of this promising therapy on inflammatory mediators and their clinical implications.
Effectiveness for herniated disc
From the September 2018 research (5): The use of ozone directly injected into the disc was explored. Among the main findings was that ozone may be beneficial because it dehydrates the disc and as such would lessen the amount of bulge pressing on the nerves. Ozone therapy also had analgesic and anti-inflammatory effects in treating disk herniation. Supplemental to this research was a 2017 study, by researchers in Italy and Canada published findings in the Journal of the Canadian Association of Radiologists (7) where they reported that patients who can benefit the most from ozone are patients with back pain with or without radicular pain but without motor deficits, which have been non-responsive to 4-6 weeks of conservative therapies. They found that short-term results could be achieved by dehydrating or shrinking the disc.
Updated research: An October 2021 paper in the journal Medical Gas Research (8) wrote: “Facet joint osteoarthritis is the most prevalent source of facet joint pain and represents a significant cause of low back pain. Oxygen-ozone therapy has been shown to have positive results in acute and chronic spinal degeneration diseases and it could be a safe and efficacious alternative to traditional facet joint conservative treatments.” Updated research: Much of the same research team from the University of Rome published a January 2024 paper, in the journal Medical Gas Research (9) in which they followed chronic neck and low back pain patients for six months to assess this use of oxygen-ozone therapy in pain alleviation. Here are the highlights of this research “Oxygen-ozone (O2-O3) therapy is considered to be an alternative therapy due to its analgesic and anti-inflammatory effects. This retrospective study evaluated the effects of Oxygen-ozone (O2-O3) intramuscular paravertebral (simply the side space between vertebrae) injections in 76 patients with chronic neck pain or low back pain, in terms of pain and disability reduction, quality of life improvement, and analgesic drug intake.”
Patients were evaluated before, at the end of the treatment, and at one, 3, and 6 months after the last treatment using standard pain, function, and disability surveys/tests. The researchers wrote: “There were significant beneficial effects of Oxygen-ozone (O2-O3) therapy in reducing pain and disability reduction and improving quality of life during the 6-month follow-up period. Oxygen-ozone (O2-O3) therapy was associated with a reduction in analgesic drug intake at each assessment.” In conclusion, the researchers reported that, based on their results, they not only supported treatment with Oxygen-ozone (O2-O3) intramuscular paravertebral injections “as a safe and beneficial treatment for chronic low back pain but also to consider it as a valuable conservative therapy for patients with chronic neck pain.”
Effectiveness for shoulder pain
From the September 2018 research: Here the researchers reported on a single case history of a 57-year-old woman who had shoulder pain reduction and increased range of motion. Next, they reported on suggested anti-inflammatory benefits in patients with shoulder adhesive capsulitis.
Updated research: A July 2023 paper in the journal Pain Physician (10) “compares the effect of ultrasound-guided intraarticular injection of ozone versus steroid versus intraarticular application of pulsed radiofrequency.” The researchers of this study from the Medical Research Institute, Alexandria University in Egypt found “Ultrasound-guided shoulder joint intraarticular injection of steroid, ozone, or pulsed radiofrequency application all result in a significant improvement in pain, disability, and range of motion in primary adhesive capsulitis . . . Comparing groups statistically, the pulsed radiofrequency group had a more delayed, but statistically better long-term improvement compared to the other 2 groups.
Effectiveness for hip bursitis
From the September 2018 research: Here the researchers suggested that ozone therapy can be used to alleviate hip pain due to functional overload, trochanteric bursitis, pain caused by initial and late coxarthrosis, and hip tendonitis. It is also helpful to associate oxygen-O3 therapy along with prescribed exercises and a period of rehabilitation.
Comparison of Ozone Therapy and corticosteroid injections for knee pain
A January 2023 paper in the journal Alternative Therapies in Health and Medicine (11) suggested that intra-articular injection of ozone, applied once a week for four weeks, resulted in a reduction in pain in stage II and stage III knee osteoarthritis, without any side effects. “However, further studies are needed to resolve the uncertainties in dosage, number of sessions, and intervals for intra-articular ozone injections.” A comparison randomized control trial published in the journal Clinical Rheumatology (12) compared the effects of ultrasound-guided corticosteroid injection with oxygen-ozone injection in patients with knee osteoarthritis. Here are the learning points:
- This double-blind randomized clinical trial was performed on 62 patients with knee osteoarthritis.
- The patients were randomly divided into two groups. In the first group 40 mg triamcinolone (steroid) and in the second group 10 cc (15 μg/ml) oxygen-ozone (O2-O3) were injected into the knee joint under ultrasound guidance.
- Pain, function, and range of motion scores were analyzed among the two groups before injection, and one week, one month, and three months after the treatment.
- Visual Analog Scale (Pain scores 0 – 10) improved in both groups.
- The improvements were seen in the Visual Analog Scale and Western Ontario McMaster University Osteoarthritis Index (self-reported pain, function, and stiffness) scores three months after treatment were in favor of the oxygen-ozone group when compared to the steroid group.
- There was no significant difference between the two groups in the range of motion and joint effusion (swelling) seen under ultrasound. However, in the oxygen-ozone-receiving group, joint effusion was decreased significantly.
- The researcher’s conclusion: “Both steroid and oxygen-ozone injections are effective in patients with knee osteoarthritis. Our study showed that the effects of oxygen-ozone injection last longer than those of steroid injection to the knee joint. “
An October 2022 review paper in the journal Anesthesiology and Pain Medicine (13) evaluated the effect of the intra-articular injection of platelet-rich plasma (PRP) and oxygen-ozone therapy to help provide an evidence-based rationale for treating knee osteoarthritis. In a review of 12 previously published articles, the researchers found after evaluation “that oxygen-ozone therapy is effective for a short time, especially in 1 – 3 months after oxygen-ozone therapy (treatment). However, after one year, it is not different from the control group. Six months following oxygen-ozone therapy, its therapeutic efficacy decreased.” As for PRP, the researchers noted superior longer-term benefits into the 6 – 12 month range.”
Ozone and steroid versus pure oxygen and steroid
An August 2023 paper in the journal Frontiers in Neurology (14) examined the clinical effectiveness of ozone combined with steroids in the treatment of discogenic low back pain. In one group of 60 patients, the treatment given was a per-paravertebral injection of a steroid mixture of 10 mL with pure oxygen 20 mL, while a second group of 60 patients received a per-paravertebral injection of a steroid mixture of 10 mL combined with ozone 20 mL (30 μg/mL). Injections were administered once a week for 3 weeks, with a follow-up of 6 months. The visual pain scores (VAS) of both groups at week one were significantly reduced compared to baseline. The improvement in reported pain was sustained at the 3- and 6-month follow-up periods. The difference between the two groups was, that the steroid/ozone mixture group had significantly lower visual pain scores at month 3 and month 6 compared to the steroid / pure oxygen group. No serious adverse events were noted in both groups.
Comparison of Ozone Therapy, Hyaluronic Acid Injections, and dextrose Prolotherapy injections
Please note that this is not a comparison of Prolozone to the other treatments, this is a comparison of ozone alone.
Prolozone is a Prolotherapy technique developed by Frank Shallenberger, MD, that utilizes ozone gas, along with other therapeutic substances to stimulate healing and reduce pain in injured soft tissues and joints. Dr. Shallenberger describes Prolozone in a 2011 article in the Journal of Prolotherapy as: “a technique that marries concepts from neural therapy, Prolotherapy, and ozone therapy. It involves injecting various combinations of procaine, anti-inflammatory medications/homeopathic, vitamins, minerals, proliferative, and a mixture of ozone/oxygen gas into degenerated or injured joints, and into areas of pain. The result of this combination is nothing short of remarkable in that damaged tissues can be regenerated, and otherwise, untreatable pain can be permanently cured.”(16)
The researchers wrote that “the existing body of evidence had well demonstrated that ozone injection was evidently effective for short-term management (1–3 months) of mild-to-moderate knee osteoarthritis patients (grade I–III KLS). But the main challenge was on longer periods of time in which different studies had declared heterogeneous (or mixed) results.”
The researchers gathered dates from a series of randomized control trials and made these observations:
- The short-term effectiveness of intra-articular ozone is better than placebo (air) and corticosteroids
- The short-term effectiveness of intra-articular ozone is equal to that of dextrose prolotherapy or hyaluronic acid injections.
- However, at 3–6 months after injections, the therapeutic efficacy of ozone decreased to a level, slightly lower than that of dextrose prolotherapy or hyaluronic acid injections.
- After 6 months, ozone therapy was not associated with significant improvement in Range of Motion and functionality
A 2015 study in the journal Anesthesiology and Pain Medicine (17) showed that:
- “Prolotherapy with hypertonic dextrose or prolozone (intraarticular ozone injection) can be effectively used in the nonoperative management of patients with knee osteoarthritis. Prolotherapy is an injection therapy for the management of chronic musculoskeletal disorders such as knee osteoarthritis. . . Ozone is a toxic and soluble gas with high oxidative activity.
- Ozone has an antinociceptive (pain-blocking) effect
- Sixty-one percent (61%) of patients with lumbar disc herniation treated with intramuscular oxygen-ozone injection became pain-free compared with 33% of the control group.
Ozone injections versus low-level laser therapy (LLLT)
An August 2021 paper published in the Journal of Lasers in Medical Sciences (18) offered a comparison between low-level laser therapy (LLLT) versus ozone therapy. In the low-level laser therapy (LLLT) group, the patients were provided with 12 sessions of low-level laser therapy. In the ozone group, 6 sessions of intra-articular injection of ozone were organized (in each session a mixture of 10 mL of bupivacaine 0.25% with 15 mL of ozone 30 μg/mL).
The researchers found: “In the middle and at the end of the treatment period in both groups, the joint pain decreased significantly . . . The study showed that both low-level laser therapy and ozone are acceptable non-invasive methods in the non-surgical treatment of knee osteoarthritis. Compared to low-level laser therapy, the ozone was more effective. These methods must be considered in any patient who is not suitable for surgical interventions or does not experience enough improvement in symptoms following long periods of common exercise training programs.”
Ozone injections combined with lidocaine
A May 2023 paper (19) from the Gaziler Physical Medicine and Rehabilitation Training and Research Hospital, in Ankara, Turkey compared the effectiveness of oxygen-ozone injection versus lidocaine injection on the trigger point in the treatment of myofascial pain syndrome.
In a study of 46 patients with myofascial pain syndrome (8 males, 38 females; average age: 45), the patients were evenly randomized (23 to a group) to either ozone injection or lidocaine injection. All injections were administered once a week for three consecutive weeks. The primary outcome measure was a reduction in pain severity. Secondary outcome measures were cervical lateral flexion range of motion (ROM), pain score (PS), and Neck Disability Index (NDI). The measurements were performed before the treatment, and at four and 12 weeks after treatment.
What the researchers found was significant positive effects on pain and disability scores in both groups. However, there was a degree of controversy as to what was the positive agent that reduced the patient’s pain and increased function. The researchers write: “Oxygen-ozone and lidocaine injections of the trigger point can effectively improve pain and functional status. However, lidocaine injection appears to be superior in reducing pain compared to oxygen-ozone injection, but is not superior in improving function. . . ”
Ozone injections in combination with dextrose Prolotherapy injections
An August 2021 study in the journal Evidence-Based Complementary and Alternative Medicine (20) examined whether ozone injections in combination with dextrose Prolotherapy injections significantly improved knee problems in patients with osteoarthritis. To do this the researchers aimed to compare the effect of hypertonic saline with ozone and hypertonic saline (as a placebo control) in improving the symptoms of osteoarthritis in the patients.
- thirty-four adults with painful primary knee osteoarthritis for at least three months were randomized to two groups: ozone plus hypertonic saline 5% and hypertonic saline 5% alone.
- Prolotherapy was given three times at baseline and then twice at two-week intervals.
The researchers found that in the saline injections with ozone and the saline injections without ozone groups, the results were about the same. Both groups did report improvements in pain, stiffness, and function. The researchers concluded: “The results showed that intra-articular prolozone therapy and hypertonic saline injection can lead to improvement of pain and function in patients with knee osteoarthritis at the same status without any significant difference.”
One study: Ozone ineffective made knee worse. Another study: “Ozone can delay the degeneration of articular cartilage (in rats)”
A December 2021 paper (21) in the medical journal Medicine, assessed various non-surgical knee osteoarthritis treatments. Among them was the use of ozone. What these researchers found was ozone injection, when compared to the other treatments, was the only intervention for which knee pain and/or function got worse at the end of the study compared with the baseline. Ozone injection showed no improvement in pain and function at 12 months.
A March 2022 paper in the medical journal Knee (22) saw researchers evaluating the effects of two different doses of gaseous ozone intra-articularly on the knee cartilage morphology in rats with osteoarthritis. The researchers found that “Intra-articular gaseous ozone can delay the degeneration of articular cartilage and can represent an integrative therapy in the osteoarthritis treatment of knee after 60 days of treatment. For the first time, the role of ozone in articular cartilage degeneration was evaluated helping to understand this therapy.”
PRP combined with ozone. A rabbit study:
Platelet Rich Plasma Therapy (PRP). Sometimes PRP is referred to as PRP Therapy, PRP injection therapy, plasma replacement therapy, or simply PRP shots take your blood, like going for a blood test and re-introducing the concentrated blood platelets from your blood into the problem joint. Your blood platelets contain growth and healing factors. When concentrated through simple centrifuging, your blood plasma becomes “rich” in healing factors, thus the name Platelet RICH plasma.
As with the previous research on rats, caution is drawn when success in animal studies do not correlate to human studies. In many animal studies, similar outcomes can be seen in humans. In some studies, similar outcomes between animals and humans are not found.
A February 2022 paper published in the Annals of Palliative Medicine (23) evaluated the effectiveness and explored the therapeutic mechanisms of the combination of platelet-rich plasma (PRP) and ozone (O3) for knee osteoarthritis. Thirty rabbits were divided into groups, one group received ozone, one group received PRP, and one group received PRP and Ozone, two other groups were used, one as control. The findings were: “PRP combined with ozone may prevent cartilage destruction and improve weight-bearing asymmetry by restoring homeostasis between anabolism and catabolism of extracellular matrix in progressive osteoarthritis (in other words stop progressive cartilage breakdown). Furthermore, a combination of PRP and ozone might achieve even better results than the two agents alone.”
Therapeutic injections of ozone into soft tissue structures, such as muscles, tendons, and ligaments as well as arthritic joints for the relief of pain have been utilized for decades in medical clinics around the world. Various case series have been published documenting the analgesic effect of ozone in osteoarthritis. Double-blind randomized controlled studies have also documented the therapeutic effects of ozone in the treatment of low back pain with and without sciatica. As a powerful oxidizing agent, ozone has been found to have a proinflammatory as well as an anti-inflammatory effect, depending on the concentration utilized. Its proposed mechanisms for tissue repair and regeneration include the stimulating of growth factor production and release.
In regard to using Ozone as the proliferant in Prolotherapy, here are my thoughts: Earlier in my career I treated many patients with Ozone therapy. I learned Ozone therapy from the then-president of the German Ozone Society (the main organization utilizing ozone therapy at the time), Gerd Wasser, M.D. Besides teaching me major autohemotherapy (a treatment where ozone gas is mixed with a patient’s blood outside the body and then injected back into the patient to kill bacteria and virus), direct ozone gas insufflations (where ozone is introduced directly into the body to fight virus), he taught me to inject ozone therapy into joints. I myself received Ozone therapy into my knee joint to try it and have utilized it on some of my patients in the past.
We have pointed out the benefits and comparisons to other treatments in ozone gas or oxygen-ozone treatments. While we do not utilize this therapy we do understand that many people have derived benefits. Why do we not use this treatment? In nearly thirty years of providing regenerative injection injections, we have had the opportunity to assess many treatments. Clinical observation and patient outcomes indicate for many treatments that their effectiveness was no better than treatments that we were already providing and the treatments themselves did not fill a need some of our patients may have had in their difficulty to treat joint pain.
We hope you found this article informative and it helped answer many of the questions you may have surrounding your chronic pain problems. If you would like to get more information specific to your challenges please email us: Get help and information from our Caring Medical staff
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This page was updated October 4, 2023