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. In this article, we will present some of the research that surrounds the use of ozone gas for problems of chronic pain.
Ozone gas started gaining attention as a treatment for chronic joint pain decades ago. 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:
- post-traumatic knee disorders,
- arthritis without marked bone deformities and
- arthritis with marked bone deformities.
- In the first two groups, optimal results were obtained while for the third other therapies were then added to stop the advancing degenerative process. In conclusion, knee joint disorders can very successfully be treated by means of an oxygen-ozone mixture locally administered.
This research is to illustrate the long years that have been dedicated to the research of ozone. We have more recent research that we will be exploring below.
The concept behind how ozone-oxygen therapy works.
In March 2021, in the journal Biomolecules (2) 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 (3) 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. (4)
Here researchers examined the role of ozone over 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
The researchers found that the use of ozone therapy has been much more effective than medication therapy in patients with the 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.
In a separate study Italian researchers writing in the International journal of molecular sciences (13) 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
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. In a 2017 study, researchers in Italy and Canada published findings in the Journal of the Canadian Association of Radiologists (5) 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.
Facet joint osteoarthritis
An October 2021 paper in the journal Medical gas research (15) 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.”
Effectiveness for shoulder pain
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.
Effectiveness for hip bursitis
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.
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/homeopathics, 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.”(6)
Comparison of Ozone Therapy and corticosteroid injections
A randomized control trial published in the journal Clinical rheumatology (7) 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. “
Comparison of Ozone Therapy and 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.
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 of Range of Motion and functionality
A 2015 study in the journal Anesthesiology and Pain Medicine (9) 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 (16) 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 LLLT. 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 LLLT and ozone are acceptable non-invasive methods in the non-surgical treatment of knee osteoarthritis. Compared to LLLT, 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 in combination with dextrose Prolotherapy injections
An August 2021 study in the journal Evidence-Based Complementary and Alternative Medicine (10) 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 (11) 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 (12) 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 “Intra-articular gaseous ozone can delay the degeneration of articular cartilage and can represents 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 takes your blood, like going for a blood test, and re-introduces 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 a human study. In many animal studies, similar outcomes can be seen in humans. In some studies similar outcomes between animal and humans are not found.
A February 2022 paper published in the Annals of palliative medicine (14) 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 has 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 (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
Brian Hutcheson, DC | Ross Hauser, MD | Danielle Steilen-Matias, PA-C
1 Sanseverino E. Knee joint disorders treated by oxygen-ozone therapy. Europa Medicophysica. 1989;3:163-170. [Google Scholar]
2 de Sire A, Agostini F, Lippi L, Mangone M, Marchese S, Cisari C, Bernetti A, Invernizzi M. Oxygen–Ozone Therapy in the Rehabilitation Field: State of the Art on Mechanisms of Action, Safety and Effectiveness in Patients with Musculoskeletal Disorders. Biomolecules. 2021 Mar;11(3):356. [Google Scholar]
3 Fusco G, Gambaro FM, Di Matteo B, Kon E. Injections in the osteoarthritic knee: a review of current treatment options. EFORT Open Reviews. 2021 Jun;6(6):501-9. [Google Scholar]
4 Seyam O, Smith NL, Reid I, Gandhi J, Jiang W, Khan SA. Clinical utility of ozone therapy for musculoskeletal disorders. Medical gas research. 2018 Jul;8(3):103. [Google Scholar]
5 Giurazza F, Guarnieri G, Murphy KJ, Muto M. Intradiscal O2O3: Rationale, Injection Technique, Short- and Long-term Outcomes for the Treatment of Low Back Pain Due to Disc Herniation. Can Assoc Radiol J. 2017 May;68(2):171-177. [Google Scholar]
6 Shallenberger F, HMD A. Prolozone™–Regenerating Joints and Eliminating Pain. Journal of Prolotherapy. 2011 May;3(2):630-8. [Google Scholar]
7 Babaei-Ghazani A, Najarzadeh S, Mansoori K, Forogh B, Madani SP, Ebadi S, Fadavi HR, Eftekharsadat B. The effects of ultrasound-guided corticosteroid injection compared to oxygen–ozone (O 2–O 3) injection in patients with knee osteoarthritis: a randomized controlled trial. Clinical rheumatology. 2018 Sep;37(9):2517-27. [Google Scholar]
8 Raeissadat SA, Tabibian E, Rayegani SM, Rahimi-Dehgolan S, Babaei-Ghazani A. An investigation into the efficacy of intra-articular ozone (O2–O3) injection in patients with knee osteoarthritis: a systematic review and meta-analysis. Journal of pain research. 2018;11:2537. [Google Scholar]
9 Hashemi M, Jalili P, Mennati S, et al. The Effects of Prolotherapy With Hypertonic Dextrose Versus Prolozone (Intraarticular Ozone) in Patients With Knee Osteoarthritis. Anesthesiology and Pain Medicine. 2015;5(5):e27585. [Google Scholar]
10 Ashraf A, Hosseini SS. The Efficacy of Ozone Prolotherapy Compared to Intra-Articular Hypertonic Saline Injection in Reducing Pain and Improving the Function of Patients with Knee Osteoarthritis: A Randomized Clinical Trial. Evidence-Based Complementary and Alternative Medicine. 2021 Aug 3;2021. [Google Scholar]
11 Naja M, Fernandez De Grado G, Favreau H, Scipioni D, Benkirane-Jessel N, Musset AM, Offner D. Comparative effectiveness of nonsurgical interventions in the treatment of patients with knee osteoarthritis: A PRISMA-compliant systematic review and network meta-analysis. Medicine (Baltimore). 2021 Dec 10;100(49):e28067. [Google Scholar]
12 Spassim MR, Dos Santos RT, Rossato-Grando LG, Cardoso L, da Silva JS, de Souza SO, Wibelinger LM, Bertol CD. Intra-articular ozone slows down the process of degeneration of articular cartilage in the knees of rats with osteoarthritis. The Knee. 2022 Mar 1;35:114-23. [Google Scholar]
13 de Sire A, Marotta N, Ferrillo M, Agostini F, Sconza C, Lippi L, Respizzi S, Giudice A, Invernizzi M, Ammendolia A. Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review. International Journal of Molecular Sciences. 2022 Feb 25;23(5):2528. [Google Scholar]
14 Huang P, Wang R, Pang X, Yang Y, Guan Y, Zhang D. Platelet-rich plasma combined with ozone prevents cartilage destruction and improves weight-bearing asymmetry in a surgery-induced osteoarthritis rabbit model. Annals of Palliative Medicine. 2021 Oct 18. [Google Scholar]
15 Latini E, Curci ER, Nusca SM, Lacopo A, Musa F, Santoboni F, Trischitta D, Vetrano M, Vulpiani MC. Medical ozone therapy in facet joint syndrome: an overview of sonoanatomy, ultrasound-guided injection techniques and potential mechanism of action. Medical Gas Research. 2021 Oct;11(4):145. [Google Scholar]
16 Fakhari S, Pishghahi A, Pourfathi H, Farzin H, Bilehjani E. A Comparison Between Low-Level Laser Therapy and Intra-articular Ozone Injection in Knee Osteoarthritis Treatment: A Randomized Clinical Trial. Journal of Lasers in Medical Sciences. 2021;12. [Google Scholar]
This page was updated July 25, 2022