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Updated Review on Ozone Therapy in Pain Medicine

Francisco Javier Hidalgo-Tallón1* Luis Miguel Torres-Morera2 Jose Baeza-Noci3 Maria Dolores Carrillo-Izquierdo4 Rosa Pinto-Bonilla3

The use of medical ozone in the treatment of chronic pain is progressively expanding in Spain and today it is used both in public and private medical centers. However, there is a great lack of knowledge about this technology not only in primary care but also in medical specialties. Although its biochemical bases are well determined and there are various systematic reviews and meta-analyses in the literature that justify its use in pain medicine, some professionals still are prejudiced against it. The evidence level of using medical ozone according SIGN (Scotish Intercollegiate Guideline Network) criteria is similar or superior to most of the techniques used in a Pain Unit. In this paper, we have done a review on ozone therapy in pain medicine, compiling the evidence published about it.

Introduction

Ozone therapy is the use of medical ozone as a therapeutic substance in pathologies with chronic hypoxia, inflammation, and redox imbalance in which ozone has proven to be effective (Baeza et al., 2015). Medical ozone is a mixture of oxygen and ozone obtained from medical oxygen by using a medical device – a medical ozone generator approved by a Notified Body according to the European Directive 93/42 and national regulations (Spanish RD 1591/2009). Medical ozone generators for parenteral use are classified in heading IIB of the classification of medical devices in EU regulations. Ozone therapy in medicine is a growing reality, and there are more and more professionals using medical ozone as a therapeutic tool for different diseases related to chronic oxidative stress and inflammation, including chronic pain.

In addition to health professional associations (such as the Spanish Ozone Therapy Association—SEOT or the World Federation of Ozone Therapy—WFOT) that try to unify criteria and develop protocols of treatment, as well as training health professionals in the use of this substance, the Catholic University of Murcia has taken the initiative by creating a chair of Ozone Therapy and Chronic Pain to better promote training and researching inside the Spanish universities network.

In Portugal and Greece, ozone therapy has a specific regulation and is used in public and private centers. In the rest of the European Union, it is used thanks to the legal recognition of medical ozone generators. In 2011, the Spanish Ministry of Health included the ozone therapy in the portfolio of services of the pain units (Palanca-Sánchez et al., 2011), so it is necessary that doctors who are experts in pain management know the rationale of medical ozone therapy and how it works, both locally and systemically.

Ozone is a molecule composed of three oxygen atoms (O3) instead of the two oxygen atoms found in the oxygen molecule (O2). Ozone has a half-life of 40 min at 20°C (Baeza et al., 2015); for this reason, it cannot be stored and must be produced “in situ” for each application.

Medical ozone applications date back to the beginning of the last century. The papers compiled in this publication have been published in the last 25 years and the oldest one have been included for historic reasons. Dr. Kellogg, in his book on diphtheria (1881) already mentioned ozone as a disinfectant, and in 1898 Drs Thauerkauf and Luth founded in Berlin the “Institute for oxygen therapy,” carrying out the first trials with animals. In 1911, the book “A Working Manual of High-Frequency Currents”, published by Dr. Noble Eberhart, head of the department of physiological therapeutics at Loyola University, described the use of medical ozone in the treatment of diseases such as tuberculosis, anemia, asthma, bronchitis, hay fever, diabetes, etc. (Pressman, 2021). But despite the successes achieved at the beginning of the last century, the ozone generating machines lacked precision and were quite fragile as they used a lot of glass tubes.

When applying this therapy, we are really inducing a controlled and harmless “micro-oxidation” that will produce a modulation of the cellular antioxidant system and the inflammation system. Ozone reacts with interstitial fluids producing hydrogen peroxide (H2O2), aldehydes, and lipid oxidation products (LOPs). These substances induce activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway that will induce an increase in antioxidant systems (ARE), such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione s-tranferase (GSTr), hem-oxygenase-1 (HO-1), reduced nicotinamide adenine dinucleotide phosphate (NADPH), NADPH quinone oxidoreductase 1 (NQO1) and heat shock protein-70 (HSP70; Baeza et al., 2015). This NRF2 activation (Figure 1) induces a decrease in the nuclear factor kappa beta (NFKβ) pathway activity, inducing an anti-inflammatory effect [decrease of interleukynes 1,2,6,7 and tumor necrosis factor alpha (TNFα) and increase of interlukynes 4, 10, 13 and transforming growing factor beta (TGFβ)] In the injected tissues, medical ozone inactivates proteolytic enzymes through the inhibition of the NFKβ pathway. At the same time, there is a proliferation of fibroblasts and chondrocytes, favoring cartilaginous regeneration (Fernández-Cuadros et al., 2020).

figure 1
www.frontiersin.orgFIGURE 1. The chemical reaction between ozone and PUFA (poli-unsaturated fatty acids) in the insterstitial water (or plasma) produce several ROS, mainly H2O2, and several LOPs, mainly 4-HNE (4-hydroxynonenal). Almost all H2O2 is kidnaped by erythrocytes (not reflected in this figure) if present. In nucleated cells, LOPs activates the NRF2 pathway, inducing the production of ARE (antioxidant response elements) and blocking the NFKB pathway. A small amount of H2O2 stimulates the NFKB pahtway, usually balanced with the NRF2 blocking action, producing a inmmunomodulation.

Several authors have published preclinical studies on the effects of medical ozone on living organisms, being able to demonstrate beneficial effects on the ability to modulate the redox balance, the cellular inflammation status, and the adaptation to ischemia/reperfusion processes (Barber et al., 1998Peralta et al., 2000Ajamieh et al., 200320042005).

From a clinical point of view, ozone therapy presents multiple medical-surgical applications, all of them related to the germicidal capacity of ozone, chronic ischemic and inflammation processes, and imbalance of the cellular redox status. Several manuals collect the experience and scientific work carried out to date by different research groups, mainly Italians, Germans, Russians, and Cubans (Bocci, 2002Menéndez et al., 2008).

The forms of application of medical ozone are basically three: topical, infiltrative, and systemic (Baeza et al., 2015). Topical applications take advantage of the germicidal power of ozone and its positive effect on the healing processes; it is usually applied directly, with the use of zip-lock bags, or by using ozonated water or ozonated oils. Infiltrated ozone at concentrations between 4 and 30 μg/ml is useful for treating musculoskeletal diseases such as arthritis, tendonitis, myositis, fasciitis, neuritis, or myofascial pain. Systemic ozone therapy consists of the administration of the mixture of gasses mainly through two routes: the indirect intravenous way (also known as autohemotherapy) and the rectal insufflation. Indirect intravenous administration consists of extracting a determined blood quantity that, within a closed circuit, is put into contact with the gas, which will dissolve and react in a few seconds, and immediately reinfused. Certified (EU marked) medical devices should be used for this procedure. Rectal insufflation consists of administering a gas enema with a probe into the rectum, where it reacts with rectal mucus and generates peroxides. These are absorbed by the mucosa, reaching the hemorrhoidal plexus and the general venous blood circulation system like any other rectal treatment. The probes must be made of silicone or other ozone-resistant plastic (OzoneSolution, 2021).

Infiltrations With Medical Ozone (O2/O3)

Generalities

The use of O2/O3 infiltrations to treat musculoskeletal pathology is increasingly widespreading. Verga (1989) was the first to describe ozone intramuscular applications at the paravertebral level and trigger points in patients with chronic low back pain. Later, in the 90s, this procedure was also used to treat acute and chronic polyarthritis (hip, knee, sacroiliac joint, and interphalangeal), tendinitis, epicondylitis, carpal tunnel syndrome, and myofascial pain (Ajamieh et al., 2005).

Despite its frequent use, the level of evidence in many of the mentioned indications, but for the treatment of lumbar disk herniation and knee osteoarthritis, is low, possibly because it has been mainly used for years in private practice where randomized clinical trials are difficult to carry out. Carmona (2005) published in 2005 a systematic review on the efficacy of ozone therapy in rheumatic diseases, concluding that there were no quality clinical trials, that most of the works were published in low-impact journals, and that the methodology between the different studies is highly variable. However, this situation is changing, as more countries are using medical ozone in public centers and universities.

Therapeutic Properties and Mechanisms of Action of Injected Ozone

When we infiltrate the oxygen/ozone mixture, we are infiltrating a highly oxidizing gas, with a good tissue diffusion capacity. Apart from the general biochemical effect described in the Introduction section, several authors have described the anti-inflammatory, analgesic, and anti-edema properties of injected medical ozone, and propose that the oxidation of the algogenic receptors would inhibit the pain signal and it would activate the antinociceptive system (Re et al., 2010). This fact has been checked in one preclinical study from Fuccio et al. (2009) by inducing sciatic damage in mice, He confirmed the corticofrontal activation of genes of caspase 1, 8, and 12 (pro-inflammatory, pro-apoptotic, and responsible for allodynia) caused by the injury; this expression was normalized with a single peripheral injection of O2/O3 around the damaged area, which also reduced mechanical allodynia.

These properties would favor a muscle relaxant effect, as well as improved mobility of the treated area that can be observed clinically (Siemsen, 1995). This fact is very important in muscle recovery with O2/O3 injections. Balkanyi (1989) has described the utility of ozone therapy in the treatment of painful muscle hypertonia, highlighting the tremendous muscle relaxant effect that is produced.

Regarding the nucleus pulposus of the intervertebral disk, several authors have described that ROS will react with amino acids and carbohydrates of proteoglycans and collagen I and II that make up the matrix, giving a lead to a process of “mummification” which would shrink the disk, reducing the compression (Hawkins and Davies, 1996Bocci et al., 2001Leonardi et al., 2001). Iliakis and his group studied the histological changes of the nucleus pulposus matrix after treatment with an ozone intradiscal injection at a concentration of 27 μg/ml in rabbits and humans (resected disk specimens using microdiscectomy after the failure of the ozone treatment). Five weeks after the injection there were no signs of perilesional chondrocytic hyperplasia or inflammatory infiltrates typically observed in herniated disks biopsies; there was a fibrous tissue of less volume (“disk mummified”), which supposes a decrease in compression on the nerve root, a decrease in venous ecstasy, an improvement in local circulation, greater oxygenation and less pain, given the great sensitivity to hypoxia of nerve roots (Iliakis et al., 2001). Similar findings in pigs at different ozone concentrations were reported by Muto (2004).

Dosage

Regarding dosage, standardized protocols are lacking. Most authors relate the amount of the gas mixture to the extension of the injury or to the size of the joint cavity to be infiltrated. Generally, the amounts of gas range between 5 and 15 ml, and ozone concentrations range from 4 to 30 μg/ml. The number of infiltration sessions usually ranges from 3 to 10 (usually one or two per week) depending on the specific evolution of each case. About intradiscal injection, 2 ml for cervical and 5 for ml is the most used amount. If a patient does not respond to treatment after two or three interventions (once every 2 weeks) it is considered a failure. Torres et al. (2009) in a 2009 publication, after having used different concentrations with the same clinical protocol, observed more improvements when intradiscal O2/O3 is infiltrated at 50 μg/ml compared to lower concentrations (25 and 30 μg/ml). Nevertheless, we recommend not reaching 50 μg/ml due to the risk of iatrogenic injuries on the ring that have been detected experimentally in pigs (Muto, 2004).

This lack of standardization in the treatment protocols makes difficult to compare results when performing a systematic review, not allowing to get high quality conclusions or recommendations.

Ozone Therapy in Knee Pathology

One of the historic references was done in 1989 by Riva (1989), that registered 156 patients with knee joint pathology (post-traumatic arthritis, knee osteoathritis with mild deformity, and knee osteoathritis with severe deformity) obtaining good results that were especially positive when there were no severe bone deformities. The treatment consisted of intra-articular and periarticular infiltrations of 10 ml of medical ozone at a concentration of 20 μg/ml.

Later, In Cuba, a prospective study was carried out in 1997 to evaluate the efficacy and safety of medical ozone injections in 126 patients with knee osteoarthritis; usually, three or four injections were needed to obtain positive results, and only 14 patients received more than five sessions. 71.4% of the patients had a good result, in 10.3% the result was fair, and in 18.3% the result was bad. The main complication was pain during infiltration. It was highlighted the economic savings due to the low cost of the infiltrations and the lesser need for anti-inflammatory drugs (Escarpanter et al., 1997). Several authors have also published their experience in case series (Delgado and Quesada, 2005Huanqui et al., 2006) and even proposed a treatment guide for based on their personal experience (Gheza and Bissolotti, 2003).

Moretti et al. (2004a) worked on the early knee osteoarthritis, comparing intraarticular injected O2/O3 with intraarticular hyaluronic acid, concluding that although there were no statistically significant differences in efficacy, ozone could be more indicated in the early stages of this disease, where inflammation predominates. In the same line, Giombini et al. (2016) published a randomized control trial comparing three kinds of injections: medical ozone, hyaluronic acid, and the combination. This last group showed the best outcomes and the hyaluronic acid group was more effective than ozone but without statistically significant differences. A systematic review and meta-analysis from Li et al. (2018) comparing medical ozone and hyaluronic acid had similar results, checking that hyaluronic acid was better than ozone but both improved the clinical status of the patients and had no significant side effects. A publication from Lopes de Jesus et al. (2017) demonstrated through a multicenter randomized, double-blind clinical trial the efficacy of intra-articular ozone injections versus placebo in knee osteoarthritis. In 2018 (Anzolin and Bertol, 2018Costa et al., 2018Raeissadat et al., 2018), 2019 (Arias-Vázquez et al., 2019Noori-Zadeh et al., 2019) and 2020 (Sconza et al., 2020), six systematic reviews and meta-analyses were published in different journals supporting the use of ozone in knee osteoarthritis with a high level of evidence (GRADE 1+; Table 1).

table 1
www.frontiersin.orgTABLE 1. Systematic reviews and meta-analysis on medical ozone in knee osteoarthritis (Anzolin and Bertol, 2018Costa et al., 2018Raeissadat et al., 2018Arias-Vázquez et al., 2019Noori-Zadeh et al., 2019Sconza et al., 2020).

These studies do not compare the results according to the radiological status of the knee, and we think this is basic fact, because hyaluronic acid is not indicated for moderate or severe knee osteoarthritis. Further studies in this line are needed to clarify the indications for medical ozone. Cost-efficacy studies are also needed as medical ozone is far cheaper than hyaluronic acid.

Other inflammatory knee pathologies have also been studied. Peritendinosus injected ozone has been used with success in refractory knee tendinopathies (Gjonovich et al., 2003). They improved 36 athletes with “jumper’s knee” who had not improved after conventional treatments.

Patellofemoral chondromalacia is a painful pathology whose treatment is mainly surgical, after which there is often aftermath. Manzi and Raimondi (2002) treated 60 patients with injected O2/O3 that had persistent pain after conventional surgical treatment, obtaining a higher and faster resolution of the pain in the treatment group compared to the control group.

Ozone Therapy in Shoulder Pathology

Gjonovich et al. (2002) published a prospective controlled study of patients suffering from subacromial tendinopathy treated with injected ozone versus mesotherapy; the ozone group showed superior clinical results. Ikonomidis et al. (2002) demonstrated in a double-blind clinical trial the greater efficacy of injected O2/O3 versus steroid injections and physiotherapy also in subacromial tendinopathy.

Oxygen-ozone therapy has also been used successfully in combination with shock waves, to treat calcifying tendinitis of the shoulder (Trenti and Gheza, 2002). Brina and Villani (2004) have published the utility of ultrasound-guided O2/O3 infiltrations in patients with non-surgical lesions of the rotator cuff. Medical ozone can increase the efficacy of other substances, as it was shown in paper of Moretti (2011) with hyaluronic acid and in paper of Gurger et al. (2021) with platelet-rich plasma (PRP); this last paper verifies the collaborative effect of ozone and PRP from a histological point of view.

Ozone Therapy in Spinal Pathology

Undoubtedly, the largest number of published works focuses on the use of ozone therapy for the treatment of herniated disks, both cervical and lumbar.

The treatment of cervical herniated disks is generally more conservative than that of the lumbar, perhaps due to the higher index of serious complications from your surgery (Wang et al., 2007). In this context, the interest in intradiscal or paravertebral medical ozone injections has special relevance, and the analgesic, anti-inflammatory, and muscle relaxant effects of the ozone therapy in cervical pathology have been described (Albertini, 2002Villa, 2002).

In 2004, Moretti et al. (2004b), conducted a clinical trial comparing the efficacy of ozone therapy versus mesotherapy in patients with neck pain, upper limb paresthesias (uni or bilateral), peripheral vertigo, and headache. One hundred and fifty two patients had hernias, protrusions, or spondylosis, 76 of which were treated with medical ozone infiltrations in paravertebral muscles, the trapezius, and the elevators of the scapula; the other 76 patients were treated with anti-inflammatory drugs and mesotherapy. The differences were statistically significant in favor of the group treated with oxygen-ozone with 78% of optimal or good results, compared to 56.25% in the group of mesotherapy.

Regarding cervical intradiscal injections, a work published by Xiao et al. (2006) also supports their efficacy. Eighty-six patients with cervical spondylosis treated with CT-guided infiltrations were retrospectively assessed. Thirty-seven suffered from myelopathy, 30 had radiculopathy and 19 had sympathetic symptoms. The indication for treatment was cervicalgia with neurological symptoms (brachial irradiation patterns, loss of tenderness, tingling, numbness, muscle weakness, or deficiency of deep tendon reflexes) and all should be refractory to conservative therapies for at least 12 weeks. Patients with cervical spinal stenosis, ossification of the posterior longitudinal ligament were excluded. The treatment with ozone therapy was excellent, good, or poor in 78, 16, and 6% of the cases, respectively, as recorded with the modified MacNab Scale. These results coincide with those published by Alexandre et al. (2005) in the same year.

In lumbar pathology the number of published works is large. The good results, along with the safety of the technique and the dreaded complications of the surgery, have made more and more authors consider ozone therapy, either paravertebral or intradiscal, the first choice in case of failure of conservative treatment.

Andreula et al. (2003) added intradiscal and periganglionic O2/O3 to the infiltration with local anesthetics and steroids; in the 6 months follow-up, by blind evaluators, a statistically significant improvement was observed with the combination of both treatments. No side effect was detected. Buric et al. (2003) did a prospective follow-up over 18 months of 104 patients with lumbosciatic pain due to disk protrusions treated with intradiscal and intraforaminal O2/O3 injections, finding improvements in pain and functional capacity in most of them. Disk volume measurements were made with MRI and it was observed that, at 5 months, 22% of the protrusions had not changed in volume, 41% had reduced the size and 37% had disappeared. The results indicated that the technique was effective in the treatment of protrusions, although the efficacy was not higher than that of the microdiscectomy, according to the authors’ experience (Buric, 2005). Also regarding disk protrusions, Qing et al. (2005), in a sample of 602 patients and 1,078 operated disks, concluded the suitability treatment with ozone therapy as the first choice after failure more conservative techniques. When comparing ozone therapy with other minimally invasive techniques, these authors considered that it was an effective, safe, and minimally stressful technique for the patient and easy to perform.

Bonetti et al. (2005), in a randomized clinical trial, compared the efficacy of intraforaminal infiltration of O2/O3 with periradicular infiltration of steroids. Three hundred and six patients with low back pain and neuropathic leg pain with and without disk disease (spondylosis, spondylolisthesis, and facet joint degeneration) were recruited and randomly divided into two groups (166 and 140). The main measuring instrument was the modified MacNab scale. Patients were evaluated in the short (1 week), medium (3 months), and long term (6 months). In short term, there were no statistically significant differences between the two treatment modalities (p = 0.4077). In long term, the differences in favor of ozone treatments were statistically significant, but only in the group of patients with disk disease (p = 0.0021); also in long term, it could be seen that ozone therapy treatments had statistically lower failure rate (8.6%) than treatments with steroids (21.4%).

Muto et al. (2008) performed CT-guided injections to 2,900 patients with lumbosciatic pain due to herniated disks (including relapses). The gas was injected intradiscal, peri-ganglionic, and periradicular. After a month the patients were reviewed, repeating the session in those cases in which the improvement was partial. At 6 and 12 months, there were improvements of 75–80% with simple disk herniation, 70% with multiple hernias, and 55% with relapses.

Equally positive results are obtained by Castro et al. (2009), in a prospective observational study in which they treated 41 patients with simultaneous intradiscal, epidural, and periradicular infiltrations. Patients with a herniated disk and free fragment and/or major neurological deficit were excluded. The evolution was very positive (according to the VAS and the Laitinen test) from the first to the last of the post-basal records (at 30 days and 6 months, respectively), and the degree of satisfaction was rated as good by 85.4% of the sample.

To clarify the long term results of this technique, Torres et al. (2009) designed a study in patients with sciatica due to herniated disc by applying three consecutive sessions of O2/O3 infiltrations once a week; the first two with an epidural [adding bupivacaine (5 ml to 0.25%) and triamcinolone (4 mg)] and paravertebral ozone and the third one, only with intradiscal ozone. The evolution of 91 patients was recorded for 24 months. A very significant improvement was achieved in 95.6% of the patients at the first-month follow-up visit, 87.7% at the first-year visit, and persisted at the end of the follow-up in 84.1% of the sample. They got one case of discitis and 11 cases of temporary headache and four cases of temporary low back pain. They found a significant reduction of the size of the hernia in 79% of the patients at 24 months MRI.

Although most of the works published refer to intradiscal injections, paravertebral injections are safer, more simple, and the most used in clinical practice, although their efficacy was under discussion. In 2006, a randomized clinical trial was published (Zambello et al., 2006) comparing the efficacy of muscular paravertebral infiltration of O2/O3 with that of epidural steroids in patients refractory to conventional treatment (oral steroids and muscle relaxants). One hundred and seventy one patients were treated with epidural steroids and 180 underwent paravertebral infiltrations of medical ozone. At the 3 weeks follow-up, the improvement was statistically significant in favor of patients treated with ozone therapy (total or almost total remission of pain in 88.2%, compared to 59% in the steroids group), and at 6 months the evolution was excellent or good in 77.1% of patients treated with ozone therapy, compared to 47.3% of patients treated with steroids.

A double-blind randomized clinical trial was conducted (Paoloni et al., 2009) to better assess the efficacy of paravertebral ozone infiltrations in the treatment of acute low back pain due to herniated disk. Sixty patients were recruited and randomized into two groups; one was treated with real infiltrations and in the other group these were simulated. Follow-up was done 15, 30, 90, and 180 days after ending the treatment. Patients treated with true ozone injections significantly improved the pain and functional limitation (p < 0.05), requiring less analgesic medication.

In 2010, a meta-analysis was published (Steppan et al., 2010) on the efficacy and safety of ozone therapy for the treatment of herniated disks. Twelve studies were included with a total sample of 8,000 patients; the mean improvements recorded were similar to those reported for discectomy: 3.9 points out of 10 on the visual analog pain scale, 25.7 points in functional capacity according to the Oswestry Disability Index and a 79.7% improvement in the records of the modified MacNab scale. The percentage of complications was 0.064%, so the treatment was considered safe and effective. Two years later, Magalhaes et al. (2012) published a systematic review and meta-analysis compiling eight observational studies and four randomized clinical trials. They concluded that the intradiscal injection to treat lumbar disk herniation has a recommendation level of 1C and that the paravertebral treatment has a recommendation level 1B according to the criteria of the US Preventive Services Task Force; this means that the recommendation is strong (maximum level), although with certain reservations for intradiscal injection due to the diversity of existing protocols.

About 80% of the population in Western countries will experience at least one episode of low back pain in your lifetime, and 55% of these will have an associated radicular pain (Long, 1991). Failed back surgery syndrome ranges between 15% and 20%, which leads to propose more conservative and less invasive treatments, such as ozone therapy, whose effectiveness seems to oscillate between 65 and 80% suggesting that a small change in disk volume can produce a large clinical change (Gangi et al., 1998). Complications of open surgery must also be taken into account, such as fibrosis, epidural and perineural tears, nerve adhesions, limitations of biomechanics due to fibrosis, and muscle paravertebral spasms and associated myofascial syndromes (Manchikanti et al., 2007). In this context, infiltrations with O2/O3, both at the paravertebral level and trigger points of related musculature and percutaneous intradiscal injection with ozone, are techniques on the rise due to their efficacy, ease of execution, low cost, and very few important side effects.

Andreula et al. (2003), when comparing ozone intradiscal injection with enzymatic nucleolysis, conclude that, with similar clinical results, treatment with ozone therapy would be the first choice due to its advantages like the ones that follow:

•There is no possibility of allergic reactions or anaphylactic

•Possibility of repeating the treatment as many times as it is considered

•Theoretical lower risk of infections, due to the germicides properties of ozone

•Possibility of using a thinner needle due to ozone fluidity and, therefore, a so much less traumatic injection

•Less post-infiltration discomfort (2, 3 days vs. 1 or 2 weeks).

To these advantages would be added those described over corticosteroids due to the absence of ozone adverse effects. In this regard, Fernández et al. (1998), in their review on the use of corticosteroids draw attention to the following points:

•Infectious arthritis

•Progressive joint deterioration

•Soft-tissue atrophy and hypopigmentation

•Tendon rupture

•Reactive synovitis due to glucocorticoid microcrystals

•Systemic adverse effects.

Some recent publications remark that the ozone administration does not close the path to surgery in case of failure (Bocci et al., 2015Muto et al., 2016).

Finally, it is worth mentioning that the efficacy of ozone therapy in the treatment of failed back surgery syndrome, highly prevalent among spine-operated patients, and usually worsens with new surgeries. In these patients, we observe fibrosis due to epidural and perineural scars, paravertebral spasms, and neural adhesions, whose chronic inflammatory stimulus would lead to neuroplastic phenomena with central and peripheral sensitization. Theoretically, the fibrinolytic, anti-inflammatory and antioxidant properties of the infiltrated O2/O3 would make it ideal for the treatment of these processes. The team from the National Medical Center 20 de Noviembre, in Mexico City, has published two papers treating 30 patients in each work. On both studies applied a first epidural injection together paravertebral infiltration followed by three weekly sessions of paravertebral infiltrations; doses of 20 ml at 30 μg/ml in the first paper and the same amount at 50 μg/ml in the second one, but the treatments could not improve patients’ pain (Grijalva et al., 2012Hernández et al., 2012). A promising alternative would be the combination of repeated paravertebral injections combined with epidural ones. Padilla del Rey et al. (2015) reported very significant improvement (VAS of 10 a 3) in a patient with refractory post-laminectomy pain who received three epidural infiltrations with ozone (10 ml at 20 μg/ml concentration) in three consecutive weeks and six paravertebral infiltrations, twice a week at the same time (10 ml at 10–30 μg/ml progressive concentration). Anyway, given the scale of the problem, more studies are needed.

Infiltrative Ozone Therapy in Rheumatoid Arthritis

A preclinical study carried out in Nanfang Hospital compared the effects of medical ozone infiltrations at different concentrations compared to oxygen; the authors showed that intra-articular ozone injected at a concentration of 40 μg/ml is capable of inhibiting synovitis in rats with rheumatoid arthritis (Chen et al., 2013). Some doctors use ozone therapy empirically in patients with rheumatic diseases using joint infiltrations for years, supposedly with very positive results, but there are no major works published in this regard.

Other Applications of Infiltrated Oxygen/Ozone

Other indications published in case series studies are tendinopathies and neural entrapment syndromes, lateral epicondylitis, rhizoarthrosis, spondylolisthesis, spondylolysis, plantar fasciitis, septic spondylodiscitis, D′Quervain’s tenosynovitis, metatarsalgia due to postsurgical fibrosis after resection of Morton’s neuroma or temporomandibular joint pathology (Bonetti et al., 20022011Gheza, 2002Gheza et al., 2002Zanardi and Zorandi, 2002Bonetti, 2003Gaffuri et al., 2003Ikonomides et al., 2003Moretti et al., 2005Alvarado, 2006Babaei-Ghazani et al., 2019).

Systemic Ozone Therapy in Pain Medicine

As mentioned, ozone therapy would be indicated as an adjuvant treatment of diseases related to disturbance of cellular redox balance or tissue oxygenation. From this point of view, systemic ozone therapy would help patients with pain chronic, as recent preclinical studies have demonstrated the role of ROS in hyperalgesia, via activation of the N-methyl-D-aspartate (NMDA) receptors. Gao et al. (2007), in a preclinical model of pain, both neuropathic and inflammatory, could demonstrate that ROS were increased at the dorsal horn in these patients, and that systemic administration of a neutralizing agent of ROS reduced the hyperalgesia by blocking phosphorylation from NMDAs. Later, the same research group (inducing hyperalgesia by capsaicin in rats) was able to demonstrate the role of the superoxide anion as responsible for abnormal pain signal processing in the dorsal horn, suggesting the therapeutic role of mitochondrial SOD-2 in these types of pain (Schwartz et al., 2009).

But certainly, the levels of scientific evidence in the treatment with systemic ozone therapy for chronic pain are practically non-existent. In this regard, a study by Clavo et al. (2013), on chronic headache refractory to triptans, found that systemic ozone improved pain and frequency of crises. Also, Fernández et al. (2016) published a work in which the use of systemic ozone therapy improved efficacy and decreased the side effects of methotrexate in patients with rheumatoid arthritis. Theoretically, the beneficial effect on immunosuppressed patients would make it useful, both in the treatment of herpes zoster infection and postherpetic neuralgia (Hu et al., 2018). In this field, several experts have tried ozone treatments for years, apparently with positive results. Ozone therapy is generally used as an adjunct to conventional treatments, either systemic or local (infiltrations or applications of oils and ozonated water; Mattassi et al., 1985Delgado et al., 1989Konrad, 2001). These studies have a low evidence level but are useful to encourage the development of better-designed works.

Fibromyalgia seems to be a “stress disease” in which underlies an alteration of the cellular redox balance, consequence of an increase in the production of free radicals, a deficiency of organic antioxidant capacity, or both simultaneously. Biochemical findings support this fact and systemic ozone therapy has been proposed (Borrelli and Bocci, 2002Hidalgo, 2012). Hidalgo et al. (2005) treated 21 patients with fibromyalgia refractory to a multidisciplinary treatment with 10 sessions of autohemotherapy, finding very good tolerability and improvement in pain and fatigue, as well as a significant decrease in the use of pain medication. This same research group (Hidalgo-Tallón et al., 2013) treated 36 patients with fibromyalgia with one daily dose of rectal ozone (200 ml of gas at 40 μg/ml) during 24 sessions, reporting significant improvements in the Fibromyalgia Impact Questionnaire, the state of mind, and the physical component of the quality of life using SF-12 scale. The treatment was very well tolerated, with transient meteorism as the most relevant adverse effect.

Systemic ozone has also been tested together with infiltrations in patients with rheumatoid arthritis. A Calunga et al. (2007) research group, published a study about lumbar disk herniation comparing paravertebral infiltrations isolated or combined with rectal ozone and checked that the combination improved all clinical parameters. In 2010, they compared (Méndez-Pérez et al., 2010) isolated O2/O3 intra-articular infiltrations (3 ml at 10 μg/ml) with the infiltrations plus rectal ozone in patients with rheumatoid arthritis of the temporomandibular joint; improvements, both in pain and in function and state of the joint capsule were statistically significant in favor of the combination therapy. In this regard, systemic ozone therapy seems to decrease in these patients interleukin 1 beta levels, directly related to disease activity, while intraarticular ozone injections would decrease intraarticular interleukin 8 levels, justifying lower granulocyte count and clinical improvement (Eastgate et al., 1988Menéndez et al., 1989Fahmy, 19931995).

Safety and Contraindications of Ozone Therapy

All authors agree on the high safety of treatments with ozone therapy, especially modern medical ozone generators with great precision.

Jacobs (1982) published that the incidence of effects adverse effects of systemic ozone therapy was only 0.0007%, mainly nausea, headache, and fatigue. In Cuba, with 25 years of experience, having at least one ozone therapy unit per province of the country, only slight adverse effects have been recorded (Bocci, 2002).

The experience of Italian experts is similar, although Dr. Bocci (Ajamieh et al., 2005) describes at least six deaths from gas applications in a direct intravenous way, a practice not recommended by scientific associations (Baeza et al., 2015).

Eventually, the most serious common adverse effect would be a vagal reaction, generally associated with pain during infiltration. It is necessary to note that the injection must be done slowly, especially if a large gas volume at a high concentration is used (Zambello et al., 2004).

However, some other complications have been reported in the literature, most of them due to malpractice or without a causal relationship between the ozone administration and the adverse event (Marchetti and La Monaca, 2000Corea et al., 2004Lo Giudice et al., 2004Ginanneschi et al., 2006Gazzeri et al., 2007Bo et al., 2009Seyman et al., 2012Vilas-Rolan et al., 2012Fort et al., 2014Menéndez et al., 2014Mustafa et al., 2015Vanni et al., 2015Cano et al., 2016Salvatore et al., 2016Balan et al., 2017Hüseyin et al., 2017Wen-Juan et al., 2017Beyaz et al., 2018Yang et al., 2018He et al., 2019). Most of them disappeared in a few days not needing specific medical treatment.

An absolute contraindication is severe glucose-6 deficiency phosphate dehydrogenase (favism), as this enzyme is necessary for supply hydrogen ions to the glutathione system, responsible for buffering the oxidation that lipoperoxides will produce in red blood cells (Viebahn, 2007).

As relative contraindications to systemic ozone therapy would be uncontrolled hyperthyroidism, thrombocytopenia, severe cardiovascular instability, and seizure states. It is also not advisable to use systemic ozone therapy in pregnant patients (Bocci, 2002) as it has not been deeply tested. Infiltrations should be avoided following the general criteria described in the literature (Sánchez et al., 2006).

Undoubtedly, ozone therapy should be practiced by a well-trained doctor and, in patients with a poor general condition, a diagnosis of the pro-oxidant/antioxidant status of the patient would be advisable.

Conclusion

For knee osteoarthritis and lumbar disk herniation, evidence on safety and efficacy from systematic reviews and meta-analysis, according the quality of the evidences proposed by the Scottish Intercollegiate Guidelines Network (SIGN), including GRADE criteria, are high (1+ and 2+ studies) and allow a recommendation level B, the same observed in most of the techniques used presently in pain units (SIGN, 2019).

However, for the rest of potential indications, the evidence level is low and ozone must be used only when other conventional treatments have failed or in a compassionate way.

Lack of standardization in treatment protocols is the Achilles’ heel of this technique, probably because of his great tolerablity that encourage doctors to explore different dosages without comparing efficacy between them. This is the main criticism in systematic reviews’ conclusions.

More RCT are needed to increase our knowledge on the indications of medical ozone, but safety profile is good enough so as to develop them. Fortunately, research interest on ozone therapy is growing, as we can check by simply doing a basic research in PubMed and watching the evolution of the number of publications in the past 20 years.

Author Contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: ozone therapy, ozone injections, medical ozone, pain medicine, chronic pain

Citation: Hidalgo-Tallón FJ, Torres-Morera LM, Baeza-Noci J, Carrillo-Izquierdo MD and Pinto-Bonilla R (2022) Updated Review on Ozone Therapy in Pain Medicine. Front. Physiol. 13:840623. doi: 10.3389/fphys.2022.840623

Received: 21 December 2021; Accepted: 24 January 2022;
Published: 23 February 2022.

Edited by:

Emma Borrelli, University of Siena, Italy

Reviewed by:

Enrico M. Camporesi, USF Health, United States
Marko Samardžija, University of Zagreb, Croatia

Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review

Elizabeth W. Bradley, Academic Editor

Associated Data

Data Availability Statement

Abstract

To date, the application of oxygen-ozone (O2O3) therapy has significantly increased in the common clinical practice in several pathological conditions. However, beyond the favorable clinical effects, the biochemical effects of O2O3 are still far from being understood. This comprehensive review aimed at investigating the state of the art about the effects of O2O3 therapy on pro-inflammatory cytokines serum levels as a modulator of oxidative stress in patients with musculoskeletal and temporomandibular disorders (TMD). The efficacy of O2O3 therapy could be related to the moderate oxidative stress modulation produced by the interaction of ozone with biological components. More in detail, O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune overactivation. In this context, most musculoskeletal and temporomandibular disorders (TMD) share these two pathophysiological processes. Despite the paucity of in vivo studies, this comprehensive review suggests that O2O3 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.

Keywords: ozone, oxygen-ozone therapy, musculoskeletal disorders, temporomandibular disorders, pain management, rehabilitation, low back pain, osteoarthritis, inflammation

1. Introduction

Ozone gas (O3) was discovered in 1840, and its expansion into the medical field has given rise to compelling research in the recent decades to validate its clinical value []. Despite some controversies, several papers [,,,,,,,,,] have proposed relevant medical features, including bactericidal and virucidal effects, inflammatory modulation and circulatory stimulation, with considerable applications in several medical fields such as wound healing, ischemic disorders, infections, and chronic inflammatory conditions such as musculoskeletal disorders.

The function of O3 shares similarities with that of a prodrug, as it is modified upon reacting with molecules to develop more active substrates, thus prompting an endogenous cascade of reactions []. On the other hand, it is hard to classify O3 as merely a prodrug, due to its power to directly interact with phospholipids, lipoproteins, bacteria envelopes and viral capsids. Therefore, O3 is considered one of the most powerful oxidizing molecules in nature, although, at high concentrations, it rapidly decomposes into ordinary oxygen []. O3 rapidly reacts with water and polyunsaturated fatty acids (PUFA) and in human fluids and tissues, producing, respectively, hydrogen peroxide (H2O2) and a combination of lipid ozonation products (LOP), mainly composed by 4-HNE (from omega-6 PUFA) and 4-HHE (trans-4 hydroxy-2-hexenal from omega-3 PUFA) []. In this context, H2O2, acting as an ozone messenger, is considered as the fundamental reactive oxygen species (ROS). However, other ROS have been identified as products of ozone reactions, such as superoxide ions and hydroxyl radical (OH) []. Hence, given the role of signal transduction, the previous concept that ROS are always harmful has recently been revised and replaced by the latest evidence describing ROS as mediators of the host defense and immune responses [].

Cytokines are undoubtedly involved in these processes and the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), macrophage migration inhibitory factor (MIF) play a pivotal role [,]. Cytokines have been considered encouraging biomarkers and clinical targets in rheumatic and oncologic therapies, but, to date, anti-cytokine-based therapeutic approaches such as the use of anti-TNF antibodies, soluble TNF receptors or IL-1 receptor antagonists have failed to ascertain a clear clinical advantage [,]. In addition, some antioxidants and ROS scavengers could exert a protecting effort against endotoxic shock in rodents by hampering TNF-α.

Thus, it has been demonstrated that ozone–oxygen (O2O3) mixture might play a key role as a microbiocidal agent compared to the rich bactericidal activity of NO, serving as a modulator of several inflammatory processes in vivo [,]. O2O3 exhibits various effects on the immune system, such as the modulation of macrophages’ phagocytic activity, which provides the first-line defense against bacteria and toxins [].

In this scenario, O2O3 concentrations should be set to a specific range to ensure safety; however, patients might present a sensation of heaviness at the injection site that spontaneously decreases in a few minutes. On the contrary, other adverse effects might be related to an incorrect administration technique, including vagal crisis, pain, hematoma in the injection site, local infections, and even death [,,].

Moreover, it has been demonstrated that low amounts of ozone increased endogenous antioxidant pathways, entangling glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), and preparing the host to face ROS-mediated physiopathological circumstances. The ozone, through oxidative preconditioning, protects tissues from ROS-related damage, promoting the antioxidant–prooxidant balance and the concomitant preservation of the cell redox state [,,]. Therefore, we could hypothesize that O2O3 mixture could enhance proinflammatory cytokine modulation [].

Musculoskeletal disorders are considered as a common cause of pain and functional disability, predicting a burden that will further increase due to the aging of the population [,,,,]. They include all inflammatory and rheumatic diseases affecting the osteoarticular system such as osteoarthritis (OA), but also low back pain and temporomandibular disorders [,,,,].

O2O3 therapy has assumed the role of an adjuvant therapeutic approach in various pathological disorders characterized by chronic inflammatory processes and immune hyper activation, and most musculoskeletal disorders share these two pathophysiological scenarios []. In this context, several authors presented a practical function of O2O3 in the management of low back pain (LBP) with promising perspectives, as a minimally invasive approach, for the conservative therapies of disc herniation or protrusion and in case of failed back surgery syndrome [,,,,,,]. At the same time, a recent systematic review [] documented that knee pain could be decreased after O2O3 intra-articular management in patients affected by knee osteoarthritis (KOA). Likewise, tendon disorders are another conceivable focus for O2O3 therapy, and a recent randomized controlled trial (RCT) evaluated the usefulness of O2O3 therapy in patients with shoulder impingement, indicating that it might be assumed an intriguing alternative intervention in case of contraindication to corticosteroids []. Moreover, O2O3 injective treatment reported positive results after O2O3 injection in patients with lateral chronic epicondylitis not responding to conventional therapy []. Lastly, favourable developments have been documented even in rheumatic diseases, where O2O3 rectal insufflations or autohemotherapy seemed to reveal a profitable safety profile, promoting positive prospective in fibromyalgia [].

A common denominator of these widespread pathologies is the low-grade inflammatory profile, with a similar serum pattern of inflammatory mediators [,,]. This concept has been recently investigated for the development of more specific and sensitive methods for early diagnosis and follow-up, starting from a detailed and targeted phenotypic characterization of musculoskeletal and temporomandibular disorders [].

To date, although it has been suggested that O2O3 therapy could be an effective analgesic treatment, its specific anti-inflammatory effects in terms of serum levels of cytokines modifications are controversial.

Several other musculoskeletal diseases might take advantage of the O2O3 therapy that is commonly used in the PRM clinical practice. However, only a few papers have investigated the effects of O2O3 therapy on other musculoskeletal disorders leading to disability (i.e., cervical pain, tendinopathies, and fibromyalgia). Moreover, it should be considered that O2O3 therapy is commonly used in the clinical practice as anti-inflammatory and analgesic therapeutic option for temporomandibular disorders (TMD) and general musculoskeletal and rheumatic diseases (Figure 1).

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Figure 1

Main clinical targets for oxygen-ozone therapy as anti-inflammatory and analgesic treatment.

Therefore, in the present comprehensive review, we aimed to investigate the state of the art about the effects of O2O3 therapy on pro-inflammatory cytokines serum levels as a modulator of oxidative stress in patients with TMD and musculoskeletal disorders.

2. Oxygen-Ozone as Anti-Inflammatory Therapy

O3 is composed of three oxygen atoms with a cyclic structure []. It is generated for medical use from pure oxygen which passes through a high voltage gradient (5–13 mV) following the reaction:

3O2 + 68,400 cal → 2O3

 

The result is a gas mixture composed of not less than 95% oxygen and not more than 5% O3. O3 is 1.6 times denser and 10 times more soluble in water than oxygen. It should be considered that O3 is the most powerful oxidant after fluorine and persulfate, although it is not a radical molecule. It is an unstable gas that cannot be stored and should be used right away as it has a half-life of 40 min at 20 °C. Despite the heterogeneous and current applications in the medical field, the biochemical effects of O2O3 are still difficult to understand, even if its properties and chemical characteristics seem to suggest some of its positive clinical effects [,,,,].

Like any other gas, O3 physically dissolves in pure water according to Henry’s law in relation to temperature, pressure, and ozone concentration. Unlike O2, O3 reacts immediately with the water present in the tissues. O3 reacts with polyunsaturated fatty acids (PUFA), antioxidants such as ascorbic and uric acid, and thiol compounds with -SH groups (cysteine, reduced glutathione-GSH and albumin). Depending on the dose of O3 administered, enzymes, carbohydrates, DNA and RNA may also be involved in the process. These compounds undergo oxidation, acting as electron donors []. O3, interacting with water and PUFA, present in the tissues, leads to the formation of hydrogen peroxide (H2O2), a fundamental reactive oxygen species (ROS) which acts as an ozone messenger, and other lipid ozonation products (LOPs) [,,].

H2O2 is a non-radical oxidant capable of acting as an O3 messenger to elicit numerous biological and therapeutic effects. The fact that ROS are always harmful is a concept widely revised in the literature as, in physiological quantities, they are considered mediators of host defense and immune responses. Moreover, they have an extremely short duration (seconds), but by virtue of their reactivity, they could damage cellular components if their generation is not well calibrated. The composition of ROS in the plasma is very rapid and is accompanied by a transient (15–20 min for the recycling of oxidized compounds) and modest decrease in the antioxidant capacity. H2O2 diffuses very easily from plasma to cells (intracellular gradient 1/10 of the plasma one) and represents an important biological stimulus. In tissues, the moderate oxidative stress of ROS is canceled by endogenous radical scavengers (superoxide dismutase, glutathione peroxidase, catalase, NADPH quinone-oxidoreductase, etc.) [,].

An excess of ROS can in fact lead to the formation of toxic compounds such as peroxynitrite (O5NOO2) and hypochlorite anion (ClO2). Furthermore, the presence of traces of Fe++ should be avoided because, in the presence of hydrogen peroxide, they catalyze the formation of the most reactive OH, through the Fenton reaction (hydroxyl radical) [].

LOPs (lipoperoxides-LOO, alkoxy radicals-LO, lipohydroperoxides-LOOH, iso-prostane and alkenes (4-hydroxy-2,3-transnonenal-HNE and malonyldialdehyde-MDA)) are signal molecules of acute oxidative stress and they cause an upregulation of antioxidant enzymes, such as superoxide dismutase (SOD), GSH-peroxidase (GSH-Px), GSH-reductase (GSH-Rd) and catalase (CAT), which play a key role in antioxidant defense. They also induce oxidative stress proteins, one of which is heme-oxygenase I (HO-1 or HSP-32), which degrades the heme molecule. Being toxic and much more stable in vitro than ROS, they must be generated in very low concentrations and metabolized by GSH-transferase (GSH-Tr) and aldehyde dehydrogenase [].

Therefore, following the administration of O3 the formation of ROS and LOP takes place and, due to their chemical diversity, they act in two different phases. ROS behave as early and short-acting messengers, while on the other hand, LOPs act as late and long-lasting messengers. Thus, they spread in different tissues and bind in small quantities to cell receptors, thus minimizing their toxicity [].

Small and repeated oxidative stresses might induce the activation of the transcriptional factor mediating nuclear factor-erythroid 2-related factor 2 (Nrf2), a domain involved in the transcription of antioxidant response elements (ARE) and usually bound to protein 1 associated with ECH Kelchlike (Keap-1), thus creating an inactive complex in the intracellular space. A mild oxidative stress can therefore favor the release of Nrf2 from this complex and its migration into the nucleus, where it would favor the transcription of different AREs on the DNA, binding to the Maf protein [,].

Therefore, through repeated mild oxidative stresses, O3 could induce the upregulation of Nrf2, conditioning human cells to transcribe different AREs, stimulating a better response to pathological radical stress, common in most chronic inflammatory diseases [].

Several antioxidant enzymes reach a higher level of concentration in response to the production of AREs, such as superoxide dismutase, catalase (CAT), glutathione-transferase (GST), heme oxygenase (HO)-1, heat shock proteins, glutathione peroxidase and quinone-oxidoreductase. These enzymes play a “scavenger role” of free radicals. Based on the redox state of the cell and the amount of O2O3 administered, we can observe different effects. For example, O2O3 overexpresses HO-1 or NO-producing 32 kPa heat shock proteins (Hsp34) and, furthermore, Hsp70 expression levels are in turn upregulated by O2O3, which is related to HO-1. Heme is enzymatically degraded by HO-1 and can be toxic depending on free iron, amount produced and biliverdin. Biliverdin is a nitrosative and oxidative stress neutralizer based on the ability to interact with reactive nitrogen and NO species. The response to thermal shock provides a cytoprotective state during an inflammatory process, aging and neurodegenerative disorders. HO isoforms appear to be regulators of cellular redox homeostasis, functioning as dynamic sensors of its oxidative stress. O2O3 may play a role in regulating the proinflammatory and anti-inflammatory effects of prostaglandin formation, which is similar in nature to NO [].

Furthermore, Nrf2 appears to play an important role in the intracellular signaling pathways of inflammation. Indeed, the activation of the Nrf2-antioxidant signal could attenuate a key regulator of the inflammatory response and muscle atrophy (NF-B), and furthermore, the literature suggests that the inflammatory response could be directly down-regulated by suppression of crucial inflammatory mediators and cytokines (IL-6, IL-8 and TNF-a) [,,].

Low doses of O3 could therefore play a role in the regulation of prostaglandin synthesis, in the release of bradykinin and in the increase of macrophage and leukocyte secretions. It is widely accepted that pain is a common symptom related to the inflammatory process and O2O3 therapy could play a key role not only in the management of inflammation, but also in nociceptive perception and modulation. As for the analgesic use of O2O3, after the administration of O2O3, an increase in antioxidant molecules (serotonin and endogenous opioids) has been demonstrated, which would induce pain relief by stimulating the antinociceptive pathways [,,,,].

Therefore, the effect of O3 mimics an acute oxidative stress that, if properly balanced, is not harmful, but is able to elicit positive biological responses and reverse chronic oxidative stress (degenerative process, aging, etc.) This hypothesis about ozone and oxidative stress modulation could be better defined as a “real non-toxic therapeutic shock able to restore homeostasis” [,,].

3. Oxygen-Ozone and Back Pain

Little evidence is available in literature about the effect of O2O3 injections in patients with low back pain due to lumbar disc herniation [,]. Although the fluoroscopy or tomography guide requirement could limit the feasibility of this therapy in conventional rehabilitation settings, positive effects were reported in comparison with other interventions such as steroid intraforaminal injection []. On the contrary, intramuscular-paravertebral O2O3 therapy seems to be safe, reliable, and effective to reduce pain in patients affected by LBP not responding to anti-inflammatory/analgesic drugs [,].

The O2O3 might exert its action combining mechanical and anti-inflammatory effects, breaking glycosaminoglycan chains in the nucleus pulposus, decreasing their capability to retain water, thus lowering the size of the herniated position, and allowing to relieve the hernial conflict [,]. A reduction in disk volume is the result of all these events. In a study conducted by Andreula et al. [], five histologic disk specimens were removed during surgical microdiscectomy, providing intradiscal injections of O3 at 27 µg/mL, and reporting the nucleus pulposus fibrillary matrix dehydration, regression, and collagen fibers revealing. Parallelly, O2O3 might also influence the inflammatory cascade by modulating the breakdown of arachidonic acid into prostaglandins and facilitating the fibroblastic action, stimulating the deposition of collagen and the initiation of the repairing process at the tissue level [].

Around the disc protrusion, inflammatory mediators prompted by granulation tissue are known to attract histiocytes, fibroblasts, and chondrocytes that can produce interleukin-1α (IL-1α), interleukin-6 (Il-6), and TNF-α; these cytokines induce the prostaglandin E2 pathway, which causes pain or increases the sensitivity of the nerve roots to other algogenic substances, such as bradykinin []. In vivo, local injection of medical ozone would increase the concentrations of TNF-α, IL1β, and IFN-γ around the disc, suggesting that the contact of medical ozone with the disc damages the extracellular matrix, resulting in shrinkage and decompression of the surrounding neurons. This might proceed probably together with the decrease in lactic acid and inflammatory cytokines, resulting in the decrease of low back pain and sciatica [].

Furthermore, this disk shrinkage can enhance local microcirculation and increase oxygen supply by decreasing venous stasis caused by disk vessel compression. The O2O3 therapy might have analgesic and anti-inflammatory effects in treating disk herniation due to the neutralization of proinflammatory cytokines by boosting the surge of antagonists’ release [].

When a disc degeneration leads to disc herniation, the adjacent nervous system structures, such as the nerve roots, or the dorsal root ganglion can be affected, causing neuropathic pain of mechanical or biochemical origin []. Moreover, other spinal structures are damaged, including facet joints, ligaments, and muscles, which can also become pain generators []. However, the peripheral sensitization should be avoided by O2O3 mediators, since recent evidence suggests that ozonized low-density lipoprotein inhibits NFkB and IL-1 receptor-associated kinase 1 (IRAK-1) signaling []. At the same time, the oxidation of IL, IL receptors, or nuclear factors might block COX-2 expression []. Clinically, Niu et al. showed that low concentrations of medical ozone (20 and 40 μg/mL) can reduce the serum IL-6, IgG, and IgM expression, presenting as analgesic and anti-inflammatory effects; while high concentrations of medical ozone (60 μg/mL) increase the serum IL-6, IgG, and IgM expression, presenting as pain and pro-inflammatory effects. Thus, the medical ozone concentration of 40 μg/mL seemed to report the optimal treatment efficacy [].

In conclusion, ozone therapy might reduce the autoimmune inflammatory reaction and, consequently, pain due to radiculopathy, after the exposure of the nucleus pulposus to the immune system []. Intramuscular O2O3 therapy is a safe and widely used procedure in the common clinical practice but these results could be only achieved starting from strict eligibility criteria in patient selection and trained and experienced physicians to perform the procedure. Nevertheless, further research must provide evidence for a correct balance between O2O3 dosage and inflammatory mediators’ expression.

4. Oxygen-Ozone and Osteoarthritis

OA is a widespread musculoskeletal disease and a leading cause of chronic disability []. Conservative estimates state that up to 240 million people worldwide suffer from it []. OA is not merely a degenerative disease, considering that both mechanical and inflammatory factors are attributed to its pathophysiology [,,]. The paradigm of OA is changing from the non-inflammatory theory of “wear and tear” to the hypothesis of “chronic low-grade inflammation” [,]. Long-time exposure to chronic low-grade inflammation and imbalance in oxidant-antioxidant systems is involved in OA pathogenesis and progression by compromising the complex network of signaling pathways that regulate cartilage and subchondral bone homeostasis [,].

A crucial role in this process might be played by inflammatory cytokines released by chondrocytes (IL-1β, IL-6, IL-8, IL-17, TNF-α, IFN-γ), promoting the catabolism of cartilage and subchondral bone [,]. Under normal conditions, these catabolic factors are in equilibrium with anabolic factors that include anti-inflammatory cytokines (IL-4, IL-10) and anabolic cytokines (TGF-β, IGF-1, FGF-18, and PDGF) [,,]. Inflammatory and catabolic factors produce an imbalance that leads a healthy joint to develop OA [].

As a result, clinical research is looking for immunomodulatory treatments that can act on inflammation to reduce the progression of OA and stimulate the synthesis of anabolic factors []. Among these, O2O3 represents a promising treatment option for its ability to modulate inflammation, promote cartilage growth, and joint repair mechanisms [,,]. O3 might influence the modulation of inflammation through different mediators and signaling pathways [,,]. In synovial fluid, O3 decreases the production of pro-inflammatory cytokines, particularly IL-6, IL-1β, and TNF-α, which are responsible for cartilage degradation []. This effect of ozone has been observed and demonstrated in several studies in animal models of knee OA (KOA), rheumatoid arthritis, and in models of ischemia/reperfusion, e.g., in the reduction of neuropathic pain [,,].

A recent in vivo study on intra-articular O2O3 injection treatment in patients with KOA has shown that O3 is capable of reducing serum levels of IL-6 []. This is particularly interesting because IL-6 is produced by IL-1β and TNF-α, two important inflammatory cytokines that appear to play a key role in the initiation and development of OA []. IL-1 is responsible for cartilage destruction whereas TNF-α activates the inflammatory process []. The authors also demonstrated that O3 could be capable of improving serum IGF-1 levels. IGF-1 is a growth factor with important properties in reducing inflammation and stimulating cell growth, differentiation, and tissue repair [].

Hashemi et al. obtained similar results showing that treatment with intra-articular injections of ozone in patients with KOA induces a significant reduction in serum levels of inflammatory cytokines at 1, 2, and 6 months after the procedure []. This result is also greater at 2 and 6 months compared with patients treated with steroid injections. Notably, IL-1b and TNF-α serum levels significantly decreased in the ozone group compared with the steroid group. The authors’ hypothesis is that ozone is likely to have a more stable anti-inflammatory effect than steroids. Although the steroid has a robust anti-inflammatory action against inflammatory cytokines, this effect in cartilage tissue was shorter than ozone. The biochemical findings of this study are also confirmed by the clinical outcomes; in fact, patients treated with ozone demonstrated a more lasting improvement in pain and disability compared to steroid injection.

These results represent in vivo confirmation of previous in vitro experiments focusing on the ability of ozone to reduce serum levels of pro-inflammatory cytokines by stimulating the production of anti-inflammatory cytokines and anabolic chemokines. These intriguing biological effects could be strictly connected to the clinical improvements observed in these patients.

Inflammatory cytokines can also increase the production of ROS which can activate the NF-Кβ pathway leading to accelerating cartilage matrix disintegration and apoptosis [,,,,]. Ozone has been observed to decrease the NF-Кβ pathway and enhance the Nrf2 (Nuclear factor erythroid 2-related factor 2) pathway, which is involved in the generation of antioxidant response elements (AREs) such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and hemoxygenase-1(HO-1) [,]. The activated NF-Кβ pathway could lead to a downstream cascade of other proinflammatory cytokines giving rise to a vicious circle that perpetuates the chronic inflammatory process []. Ozone inhibition of NF-Кβ activation can reduce the degradation of the cartilage matrix and initiation of the apoptotic pathway, thus supporting cell survival [] (Figure 2).

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Figure 2

Ozone (O3) intracellular and intranuclear pathways involved in inflammation and oxidative stress.

Although injured or damaged articular cartilage remains one of the most difficult tissues to treat [], it has been recently highlighted that the ozone could provide promising results as a safe and effective treatment in patients with KOA from both a biochemical and clinical perspective [,,,,,,,,].

5. Oxygen-Ozone and Rheumatic Diseases

Rheumatoid arthritis (RA) is the most frequent pathology associated with chronic joint inflammation, a genetic degenerative disease that initially affects extremity joints and is characterized by a chronic inflammatory state that distorts and demolishes articular cartilage and expands connective tissue fibrosis, leading to cell destruction and subchondral bone deterioration. It has been estimated that about 1% of the world population suffers from this disorder []. O2O3 therapy effectively decreased inflammation with a down-regulation of pro-inflammatory cytokines and an up-regulation of IL-10 anti-inflammatory cytokine []. Rajesh and collaborators investigated the temporal expression of cytokines during the initial phase of an experimental model of arthritic inflammation and revealed that interferon-gamma (IFN-γ) participates in inflammatory process modulation []. The O3 has also been shown to effectively increase the clinical response of methotrexate (MTX) in patients with rheumatoid arthritis induced by PG/PS. The combination therapy diminishes inflammation through reduction of IL-1B and TNF-α and decreases oxidative stress by reducing hydrogen and preventing damage to proteins and lipids [].

In this scenario, O2O3 therapy seems to play a positive role in several inflammatory conditions due to its bacteriostatic, oxidative stress, immune and epigenetic modulation. Compared with topical ozone administration, systematic ozone therapy has apparent advantages in enhancing metabolism, blood hypercoagulability, angiosclerosis, insomnia, and rejuvenation of the body [,]. Thus, psoriasis vulgaris is a chronic immune-mediated inflammatory cutaneous disease characterized by red, itchy, and scaly skin patches. Patients typically suffer disfiguration, disability, and associated comorbidities []. Zeng et al. indicated that short-term O2O3 therapy seemed to attenuate psoriatic disease severity lowering the level of blood lipids and up-streaming PPAR-γ level in CD4 T cells, considering that the PPAR-γ expression is commonly reduced in CD4 T cells in psoriasis [].

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease, characterized by skin and visceral organs fibrosis and vasculopathy [,]. Carpal tunnel syndrome (CTS) is one of the most common entrapment disorders in general and the most recurring peripheral nervous system involvement in SSc [,]. Elawamy et al. demonstrated that both intracarpal ozone or methylprednisolone reported advantageous impacts upon CTS in people with SSC; nonetheless, ozone relieves pain, enhances the hand functioning, decreases the duration and frequency of Raynaud’s attacks, declines the size of ulceration, and improves median nerve conduction study over the 6-month follow-up []. Rascaroli et al. found slight improvements in sensory and motor parameters after ozone therapy, and Bahrami et al. showed improvement of median sensory nerve action potential latency, compared to the pre-treatment level in both groups (one group treated with wrist volar splint alone, the other group treated with ozone injection and splint) [,,,]. The nature of the fibrotic expression in SSc people with CTS seemed to be significantly associated with gene upstream for Col1 and Col3, TGF-β, and SMAD3 in CTS fibroblasts [,]. These studies, focusing on TGF-β signaling inhibition in CTS, reported that therapies targeted for the TGF-β pathway might eventually have utility for the prevention and treatment of CTS, as well as the anti-fibrotic effect of relaxin [,].

Gout disease is one of the most frequent causes of inflammatory arthritis in adults and is chronic disorder associated with self-limiting acute gout attacks (gout flare), caused by the accretion of monosodium urate (MSU) depositions in joints and surrounding soft tissue and bursa [,,]. Acute episodes of gout disease are one of the most influential reasons for unfavourable health-related quality of life [,,]. In a rat model, ozone therapy indicated a decrease in the degree of edematous ankle swelling, pro-inflammatory cytokines, lipid peroxidation, the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3), procaspase-1, caspase-1, interleukin-1β synovial tissue levels with an enhancement of antioxidant defence system []. In other murine models, Bilge et al. demonstrated that ozone therapy raises the levels of antioxidant enzymes, including oxidative shock proteins (hemo-oxygenase-1), Interleukin 4 and Interleukin 10, TGF-β, NO endorphin, adrenocorticotropic hormone (ACTH), and cortisol levels [].

In conclusion, the positive effect of ozone treatment sustained by its bidirectional regulation of immunity are present also in rheumatic diseases patients. These positive effects could be caused by a O2O3-related massive production of inflammatory modulation cytokines by immune cells.

6. Oxygen-Ozone and Temporomandibular Disorders

Temporomandibular disorders (TMD) represent heterogeneous musculoskeletal disorders, defined as a multifactorial set of signs and symptoms involving masticatory muscles of the stomatognathic system, temporomandibular joint (TMJ), or both [].

According to the Diagnostic Criteria for TMD (DC/TMD) Axis I, TMD could be divided in muscle disorders (including myofascial pain) or intra-articular disorders (including disc displacement with or without reduction, arthralgia, and arthritis) [,].

TMD are the second most common musculoskeletal disorders, affecting approximately 90% of the general population [,,]. Indeed, TMD are the first most common cause of pain of non-dental origin in the maxillofacial region [], with an incidence rate of 3.9% per annum [].

Main clinical symptoms are pain and limited jaw range of motion, often accompanied by decrease in the maximal interincisal opening, muscle or joint tenderness on palpation, joint sounds, and otologic complaints (e.g., tinnitus, vertigo, or ear fullness) [,]. These signs and symptoms could lead to discomfort or difficulty in performing activities of daily living, such as eating, chewing, talking, swallowing, yawning, causing disability with a significantly reduced quality of life [,,].

The etiology has been accepted as multifactorial, and parafunctional habits, clenching of teeth, grinding, as well as psychosocial issues, including anxiety depression are generally believed to contribute to the development or perpetuation of the pain complaints [,,,].

In response to this imbalance of the masticatory system, cytokines such as TNFα, IL-1, IL-6 and IL-8 are released within TMJ [], thus promoting the release of proteinases and stimulating the expression of degrading enzymes and inflammatory mediators; all this mechanism could lead to a TMJ inflammation and bone and cartilage degradation []. Other cytokines and metallo-proteinases (MMPs) could be involved in the inflammatory process, including interferon-gamma (IFN-γ), prostaglandin E2 (PGE2), IL-17, MMP-2, MMP-9, aggrecanase-1 and aggrecanase-2 [,,,].

More in detail, both immune and non-immune cells could release TNF-α (e.g., macrophages, synoviocytes, and neurons associated with the trigeminal ganglion), causing TMJ inflammation and pain in myofascial TMD patients []. Ulmner et al. [] characterized and quantified the synovial tissue cytokines and related the result to the diagnoses of disc displacement with or without reduction. Results of this study showed that bone morphogenetic protein (BMP) type 2 and 4, epidermal growth factor (EGF), eotaxin, granulocyte-colony stimulating factor (G-CSF), IL-1β, IL-7, IL-8, IL-10, macrophage inflammatory protein (MIP) 1β, TNF-α and TNF-β had significantly higher concentrations in patients with disc displacement without reduction. In 2021, Son et al. [] investigated the relationship between long-term clinical characteristics and different cytokine and autoimmunity levels in young female TMD patients according to pain disability. The subjects included in the study were classified in high and low disability groups, according to the Graded Chronic Pain Scale (GCPS). The authors showed that IL-8 and IgG levels were significantly higher in the high disability group (p = 0.047 and 0.005, respectively).

Several conservative treatments have been used for reducing TMD-related pain, including occlusal splint devices [,], behavioral therapies [], manual therapy [], laser therapy [], transcutaneous electrical nerve stimulation (TENS) [], dry needling []. In this context, O2O3 therapy [,,,] might be considered as a promising new treatment to reduce TMD pain, although the mechanism of action should still be adequately investigated []. Probably, O2O3 might effectively decrease inflammation with a down-regulation of pro-inflammatory cytokines and an up-regulation of IL-10 anti-inflammatory cytokine [].

In the context of muscle-related TMD, Celakil et al. [] recently conducted a double-blind randomized clinical trial in order to evaluate the efficacy of ozone therapy compared to placebo. Topical gaseous ozone therapy was applied to the muscles of 20 participants three times per week for 10 min for 2 weeks, with a significantly lower VAS score than placebo group after treatment (p = 0.040). Moreover, the pressure pain threshold of the temporal muscle, masseter muscle, and TMJ lateral pole were significantly higher in the ozone group (p = 0.035; p = 0.007; p = 0.012, respectively). The same authors also compared the bio-oxidative ozone therapy to occlusal splints therapy in patients affected by both muscle and articular TMD disorders [,,], showing that both therapies were effective in the improvement of mandibular movements and VAS scores. However, evaluating the effects in terms of PPT measurement of the temporal and masseter, their results indicated that occlusal splint treatment produced better results than ozone application (p = 0.046; p = 0.024, respectively). In the context of intra-articular TMD, Daif et al. compared the effects of TMJ ozone injections to medication therapy in TMD patients with disc displacement with reduction []. In the ozone group, each joint received 2 mL ozone–oxygen mixture (10 μg/mL) injections, 2 times per week for 3 weeks, whereas patients in the second group received nonsteroidal anti-inflammatory drugs and muscle relaxants showing. Results of this study showed that 87% of the patients who received ozone gas injections into the superior joint space either completely recovered (37%) or improved (50%), whereas in the medication group, only 33% of the patients showed an improvement in their clinical dysfunction indexes.

To date, the precise mechanism underpinning the positive effects of O2O3 therapy in TMD patients are far from being understood. However, O3 decreases the production of pro-inflammatory cytokines, particularly IL-6, IL-1β, and TNF-α, which are responsible for cartilage degradation in the synovial fluid []. Thus, when injected into a joint capsule, O2O3 could be able to stimulate the intrinsic fibroblastic joint repairing abilities and to promote new cartilage growth as well as reducing inflammation [,]. Therefore, ozone therapy is a not-invasive, fast, and comfortable treatment modality that seems to be effective in the pain management framework in TMD. This could have positive implications for these patients in improving mandibular function, although the precise role of O2O3 on serum levels of pro-inflammatory cytokines should be better investigated.

7. Conclusions

In conclusion, this comprehensive review describes the impact of O2O3 therapy on serum cytokine levels in different settings and conditions. As previously described, musculoskeletal and rheumatological disorders include several pathological conditions characterized by different and complex therapeutic approaches. In this scenario, O2O3 therapy remains a promising conservative and minimally invasive intervention that improves pain symptoms and patients’ quality of life. To date, evidence suggests a role of O2O3 therapy in IL-6 and IL-10 serum level modulation, although the precise epigenetic mechanism remains controversial. Therefore, further high-quality studies are needed to fully understand the molecular, epigenetic, and biochemical effects of O2O3 and its therapeutic implications.

Author Contributions

Conceptualization, A.d.S.; methodology, A.d.S.; formal analysis, N.M., M.F., F.A., C.S., and L.L.; data curation, A.d.S., S.R., A.G., M.I. and A.A.; writing—original draft preparation, A.d.S. and N.M.; writing—review and editing, M.I. and A.A.; visualization, M.F., F.A., C.S., L.L., S.R. and A.G.; supervision, A.d.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

 

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Cranial Neuritis: Therapeutic Effects of Prolotherapy

Cranial neuritis is a condition that is characterized by inflammation or injury to the cranial nerves. Those who are affected by this ailment may experience substantial discomfort and have their normal daily activities disrupted. Prolotherapy is an emerging alternative therapy that should be considered together with the many other treatment alternatives that are now available. In this piece, we will delve into the world of cranial neuritis, investigating its causes as well as its symptoms and the traditional treatments that are available for it. In addition, we will investigate the function that prolotherapy may play in the treatment of cranial neuritis as well as the potential benefits it may offer.

Cranial neuritis is the inflammation or injury of one or more of the cranial nerves. These nerves are responsible for the transmission of sensory and motor information to and from the head and neck. Cranial neuritis can be caused by a number of different conditions. This illness can present itself in a variety of different ways, leading to symptoms such as severe headaches, facial pain, vision changes, dizziness, or hearing difficulties. Cranial neuritis can have a variety of origins, such as bacterial or viral infections, autoimmune diseases, traumatic injuries, or even the result of nerves being compressed.

When a patient has been diagnosed with cranial neuritis, traditional treatment methods are typically implemented. These methods are targeted at lowering inflammation, managing pain, and fostering nerve recovery. Depending on the severity of the condition, they may include anti-inflammatory drugs, pain relievers, physical therapy, or even surgical procedures. Even though these treatments have the potential to alleviate symptoms, they may not always get to the bottom of what's causing the problem or deliver the outcomes that are sought for every person.

Prolotherapy is a minimally invasive method that is gaining prominence as an alternative therapeutic option for a variety of disorders affecting the musculoskeletal system, including cranial neuritis. It is also known by the name regenerative injection therapy. A solution, which is typically a mixture of dextrose or another irritating material, is injected directly into the area that is afflicted as part of the procedure. The purpose of the solution is to activate the body's natural healing reaction, so facilitating the restoration of injured tissues, ligaments, and tendons and enhancing their strength.

Individuals who are diagnosed with cranial neuritis may stand to profit from prolotherapy in a number of different ways, according to proponents of the treatment. First, the goal of prolotherapy is to regenerate damaged nerves by activating the natural healing mechanisms of the body. This, in turn, should promote nerve repair and reduce inflammation. It is possible that patients will experience less pain as a result of this, as well as improved function and an overall improvement in their quality of life.

Additionally, due to the regenerative properties of prolotherapy, it may be possible to address the underlying causes of cranial neuritis, thereby addressing the issue at its source rather than merely treating the symptoms. Prolotherapy may be able to assist treat the structural imbalances or weaknesses that are contributing to nerve inflammation and irritation. It does this by encouraging the healing and strengthening of tissue.

Cranial neuritis can have a substantial negative impact on a person's health by creating symptoms that are incapacitating and by interfering with daily life. Exploring alternative treatments such as prolotherapy, which may give new alternatives for the management of cranial neuritis, while conventional treatments provide relief for many people who suffer from cranial neuritis. Prolotherapy has the ability to enhance nerve healing, reduce inflammation, and correct underlying structural imbalances due to its regenerative nature. However, it is absolutely necessary to confer with medical experts in order to ascertain whether or not prolotherapy is appropriate for a particular patient's condition and whether or not it is likely to be beneficial.

The office of Dr. Alvin Philipose can be reached at (405) 848-7246.

Autoimmune diseases are difficult conditions characterized by a hyperactive immune response against the body's own tissues. Mast cells, vital immune system components, have been found to play a significant role in the onset and progression of autoimmune diseases. Ozone therapy has emerged as a possible therapeutic option as researchers continue to investigate alternative therapies. In this article, we will examine the relationship between mast cells and autoimmune diseases, as well as the use of ozone therapy as a novel method for their treatment.

Understanding Mast Cells and Immune System Disorders

Mast cells are immune cells that are predominantly found in tissues that come into contact with the external environment, such as the epidermis, respiratory system, and digestive system. They possess receptors capable of recognizing pathogens, allergens, and other triggers. In autoimmunity, mast cells can become hyperactive and cause the excessive release of histamine, cytokines, and other inflammatory mediators, resulting in chronic inflammation and tissue injury.

Mast cells have been implicated in a variety of autoimmune diseases, including:

Mast cells are present in the synovial fluid and tissue of affected joints in patients with rheumatoid arthritis. Their activation contributes to the inflammatory response and joint degeneration characteristic of this condition.
Mast cells participate in the immune response in Systemic Lupus Erythematosus (SLE) and are associated with the release of autoantibodies and pro-inflammatory molecules, thereby exacerbating tissue injury and organ involvement.
Mast cells serve a role in the neuroinflammatory processes of multiple sclerosis (MS). Their activation may contribute to the collapse of the blood-brain barrier and the infiltration of immune cells into the central nervous system.
Ozone Therapy: A Different Method

Alternative medicine ozone therapy entails the administration of ozone gas to promote healing and modulate the immune system. Ozone is a highly reactive form of oxygen that may have anti-inflammatory, immunomodulatory, and antimicrobial effects on the body. Here are the potential benefits of ozone therapy in the context of autoimmune diseases and mast cell involvement:

It has been discovered that ozone therapy modulates mast cell activation and reduces the release of inflammatory mediators such as histamine and cytokines. Ozone therapy may alleviate the chronic inflammation associated with autoimmune diseases by modulating mast cell function.
It has been demonstrated that ozone therapy decreases the production of pro-inflammatory molecules while increasing the production of anti-inflammatory substances. This change in the immune response has the potential to assist in regulating the excessive inflammation observed in autoimmune diseases.
Immune System Regulation Ozone therapy has immunomodulatory effects, which means it can balance and regulate immune system activity. By fostering a balanced immune response, ozone therapy may prevent the immune system from attacking healthy tissues, which is a defining characteristic of autoimmune diseases.
Enhanced Oxygen Utilization Ozone therapy can enhance the cellular oxygen utilization. Improved oxygen delivery and utilization can support tissue repair and boost overall cellular function, which may be advantageous for autoimmune patients.
While ozone therapy shows promise as an alternative treatment, more research is required to ascertain its safety, efficacy, and optimal protocols for treating various autoimmune conditions. To ensure appropriate administration and monitoring, it is vital to consult with a qualified healthcare professional at Venturis in Oklahoma City with experience in ozone therapy.

Ozone therapy has been gaining popularity in recent years as a natural and non-invasive treatment option for a variety of health conditions. It involves the administration of ozone gas, which is made up of three oxygen atoms, to the body to improve oxygen delivery and promote healing. However, many people are not aware that there are different types of ozone therapy available. In this blog post, we'll explore the different types of ozone therapy and what they are used for.

  1. Major Autohemotherapy (MAH)

Major Autohemotherapy (MAH) is one of the most common types of ozone therapy. It involves withdrawing a small amount of the patient's blood, mixing it with ozone, and then reintroducing the ozonated blood back into the patient's bloodstream. This type of therapy is used to improve circulation, boost the immune system, and promote healing.

  1. Rectal Insufflation

Rectal insufflation is a type of ozone therapy that involves the administration of ozone gas through the rectum. This method is typically used to treat digestive disorders, such as irritable bowel syndrome, and to improve overall gut health.

  1. Ozone Sauna Therapy

Ozone sauna therapy involves the use of a special sauna that infuses ozone gas into the air. The patient sits in the sauna and inhales the ozonated air, which is believed to improve circulation, boost the immune system, and promote detoxification.

  1. Ozonated Water

Ozonated water is created by bubbling ozone gas through water, which creates ozonated water. This type of therapy is typically used to treat skin conditions, such as eczema and acne, and to promote overall skin health.

  1. Ozone Injection Therapy

Ozone injection therapy involves the direct injection of ozonated saline into specific areas of the body, such as joints or muscles. This type of therapy is typically used to treat pain and inflammation.

  1. Bagging

Bagging is a type of ozone therapy that involves placing a plastic bag over a specific area of the body, such as a limb, and infusing ozone gas into the bag. This method is typically used to treat wounds, infections, and skin conditions.

It's important to note that while ozone therapy is generally safe, there are some risks associated with the treatment. Patients should speak with a healthcare provider to determine if ozone therapy is right for them and which type of therapy would be best for their specific health concerns.

Ozone therapy is a natural and non-invasive treatment option for a variety of health conditions. There are different types of ozone therapy available, each with its own specific uses and benefits. Patients should speak with a healthcare provider at Venturis Clinic in Oklahoma City to determine which type of ozone therapy would be best for their individual needs.

Ozone infusion therapy has been gaining popularity in recent years as a treatment for various health conditions. It involves the infusion of Vitamins, ozone, a gas made up of three oxygen atoms, into the bloodstream to improve oxygen delivery and promote healing. However, the cost of this therapy can be quite high, leaving many wondering if it's worth the investment. In this blog post, we'll explore the cost of ozone infusion therapy and whether it's worth it for patients.

Firstly, it's important to understand that the cost of ozone infusion therapy can vary depending on a number of factors, including the location of the clinic, the credentials of the healthcare provider administering the therapy, and the number of treatments needed. On average, a single session of ozone infusion therapy can cost anywhere from $200 to $1000.

While this cost may seem steep, it's important to consider the potential benefits of Vitamin ozone infusion therapy. Ozone therapy has been shown to have a number of health benefits, including improved circulation, increased oxygen delivery to tissues, and enhanced immune function. It has been used to treat a variety of conditions, including chronic pain, autoimmune disorders, and infections.

In addition, ozone therapy is a non-invasive treatment option that is generally well-tolerated by patients. It has few side effects and does not require any downtime, making it a convenient option for those with busy schedules.

However, it's important to note that ozone therapy is not a one-size-fits-all solution. Patients should speak with a healthcare provider to determine if ozone infusion therapy is right for them and their specific health concerns. Additionally, while ozone therapy is generally safe, there are some risks associated with the treatment, including the potential for infection or allergic reaction.

Ultimately, the decision to pursue ozone infusion therapy should be based on a variety of factors, including the potential benefits of the treatment, the patient's specific health concerns, and their budget. While the cost of ozone therapy can be high, the potential benefits may make it worth the investment for some patients.

In conclusion, ozone infusion therapy is a promising treatment option for a variety of health conditions, but it comes with a cost. Patients should carefully consider the potential benefits and risks of the treatment, as well as their budget, before deciding whether to pursue ozone therapy. As always, it's important to speak with a healthcare provider at Venturi Clinic in Oklahoma City to determine the best course of treatment for your individual needs.

If you have tried multiple types of doctors and treatments but still hurting, you may not have found the cause. We can help!
Find Us
7917 N May Ave, Oklahoma City, 
OK 73120, USA
(405) 848-7246
info@venturisclinic.com
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