Successful treatment of a high-risk diabetic foot ulcer by ozone therapy and collagen powder: A case report.

Key Clinical Message: A high risk diabetic foot ulcer is treated by ozone therapy and collagen powder. The goal of this study was to report a high risk case, treated by ozone therapy, and collagen powder. Ozone therapy and collagen powder can improve healing process of diabetic foot ulcers. Abstract: This case report presents a successful nonsurgical outpatient approach for managing a high-risk diabetic foot ulcer with tendon exposure in an older adult with uncontrolled diabetes mellitus and severe heart failure. Due to the patient's comorbidities, surgical intervention was not an option, leading to the utilization of ozone therapy, collagen powder, and Phenytoin ointment. The significance of this case lies in the treatment of a high-risk foot ulcer through a nonsurgical approach, considering the patient's uncontrolled diabetes and severe heart failure. Diabetic foot ulcers (DFUs) are debilitating and life-threatening complications, often resulting in amputations, socio-psychological burdens, and lifestyle changes. Conventional treatment methods have shown limited success, necessitating the exploration of new and innovative approaches. The use of ozone therapy has emerged as a potential treatment, but its safety and efficacy in DFUs require further investigation. The positive outcomes observed in this case report suggest that ozone therapy may be a viable option for treating DFUs, and further studies are recommended to evaluate its effectiveness.

Oxygen-ozone therapy for pain relief in patients with trapeziometacarpal osteoarthritis: a proof-of-concept study.

PURPOSE: Trapeziometacarpal osteoarthritis (TMC-OA) is a prevalent hand disorder affecting a growing number of people worldwide. While a multidisciplinary approach might provide additional advantages, the analgesic and anti-inflammatory role of intra-articular oxygen-ozone (O2O3) injections combined with physical therapy is still unknown. To assess the impact of a multimodal therapeutic approach combining O2O3 injections with physical therapy in patients with TMC-OA. MATERIALS AND METHODS: A prospective open-label study conducted in the Physical and Rehabilitation Medicine Unit of the "Renato Dulbecco" University Hospital of Catanzaro. We assessed patients with TMC-OA who had not responded to standard medical therapy. Participants received O2O3 therapy and targeted physical therapy for 4 weeks. Pain relief, muscle strength, and physical functioning were assessed at baseline and after 4, 12 and 24 weeks (respectively T0, T1, T2, and T3). RESULTS: Seventeen patients with a mean age of 67.1 ± 6.1 years were included in the study. Short-term improvements in pain intensity were observed (T0: 6.221 ± 1.514; T1: 3.172 ± 1.1451; p < .001) and were maintained over a 24-week follow-up period (T0: 6.221 ± 1.514; T3: 4.393 ± 1.438; p: 0.006). Significant changes were reported also in terms of muscle strength and physical functioning. O2O3 therapy was well-tolerated with no adverse effects. CONCLUSIONS: A combination of O2O3 injections and physical therapy might be considered in patients with TMC-OA. Further investigation is warranted to assess the effectiveness of O2O3 therapy in managing TMC-OA.

The addition of intra-articular trapeziometacarpal O₂O₃ injections to physical therapy is safe and reliable for thumb osteoarthritisO₂O₃ injection could be considered a second-line mini-invasive approach option when simple analgesic and non-pharmacologic interventions have failed, and surgical treatment is not yet indicatedO₂O₃ injections in combination with physical therapy may provide benefits in terms of pain relief in patients with TMC joint OA in whom previous conventional medical therapy has been unsuccessful.

Clinical Outcome for Lumbar Disc Herniation Treatment with Intradiscal Oxygen-ozone Therapy.

BACKGROUND: Low back pain due to disc herniation is a common problem causing frequent hospital visits and loss of working days with major socio-economic impact. Conservative treatments like analgesics, physiotherapy do not work in all patients. Surgical treatment has been the mainstay of treatment when indicated but is associated with anesthetic and surgical complications. Intradiscal oxygen-ozone chemonucleolysis is a minimally invasive procedure done under local anesthesia and has promising role in shrinking the bulged disc and reducing nerve root compression and related symptoms. This retrospective study was done to see how intradiscal oxygen-ozone chemonucleolysis reduces pain severity in patients with discogenic low back pain. METHODS: Retrospective data were retrieved of those patients who underwent fluoroscopy guided intradiscal oxygen-ozone chemonucleolysis with 5-6 ml of an O2-O3 mixture (concentration of 30 microgram/ml) during a period of two years in Nepal pain care and research center. Numerical pain scale (NRS) at various follow ups were compared to preprocedural NRS. RESULTS: Preprocedural NRS was 8± 13. NRS at three hours, one week, one month, three months and six months were 2± 13 (73 percent reduction), 2± 53 (68 percent reduction), 2± 27 (72 percent reduction), 1± 08 (77 percent reduction) and 1± 67 (79 percent reduction) respectively. CONCLUSIONS: Intradiscal oxygen-ozone chemonucleolysis can be a useful modality of treatment for discogenic low back pain in patients who fail to respond to conservative management and in whom surgery is not indicated.

Use of Ozone Therapy and Thymoquinone in the Prevention of Formaldehyde Toxicity by Inhalation: An Experimental Study.

INTRODUCTION: The study determined the damage caused by formaldehyde (FA) exposure in blood and liver samples using biochemical markers. Histopathological analysis was performed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method and measurement of CD68 cell density. To what extent the antioxidant molecules thymoquinone (TQ) and ozone (O3) reversed the damage caused by FA exposure was investigated, both when used alone and combined. METHODS: Fifty-six Sprague-Dawley male rats of eight to ten weeks of age were used in the experiment. The rats were divided into eight groups, with seven rats in each group: the untreated control group, the group treated with TQ (10 mg/kg/day), the group treated with O3 (150 µg/kg/day), the group treated with TQ+O3, the group exposed to FA (10 ppm 8 h/day), the group receiving FA+TQ, the group receiving FA+O3, and the group receiving FA+TQ+O3. Serum aspartate transaminase (AST), alanine transaminase (ALT), total antioxidant (TAS, U/mL), and total oxidant (TOS, nmol/mL) levels were analyzed. TAS and TOS levels, CD68 cell density, and apoptotic cells were determined in liver tissues. RESULTS: FA exposure caused an increase in serum AST and ALT levels of (p<0.05) experimental animals, a decrease in TAS levels in serum (p=0.03) and liver (p>0.05) and an increase in TOS levels (p>0.05), TUNEL positivity (p<0.001), and CD68 cell density (p=0.004). Administration of TQ and O3 as antioxidants significantly reversed biochemical and histopathological alterations in the serum and liver. CONCLUSION: TQ and ozone therapy suppressed oxidative stress caused by FA exposure and reversed the emerging histopathological deteriorations. Ozone therapy did not suppress the effects of TQ. Therefore, ozone therapy can be given as a supportive therapy along with the main therapeutic agents. We think TQ and ozone therapy may be useful to protect individuals exposed to FA.

Ozone Therapy for a Soccer Player With Osteitis Pubis: A Case Report.

CONTEXT: Osteitis pubis (OP), which occurs as a result of excessive use of the symphysis pubis and parasymphysis bones, is more common in long-distance runners and kicking athletes, especially football players. Due to the poor results of commonly used treatments for OP, there is a need for investigation of more effective treatments, such as ozone therapy. Ozone therapy is used to treat a variety of diseases, including musculoskeletal conditions. CASE PRESENTATION: A 30-year-old amateur soccer player diagnosed with OP received conservative treatment with traditional physiotherapy and analgesic medications. After 6 months and no resolution of symptoms, the patient presented to the sports medicine outpatient clinic seeking alternative therapy options. MANAGEMENT AND OUTCOMES: The patient received ozone injections in 3 sessions administered at 10-day intervals. At 1, 3, 6 and 12 months after the treatment, the patient's complaints and pain levels were re-evaluated and examined. The patient was able to return to competition at the same level after the first injection. No recurrence was revealed at a minimum of 12 months of follow-up. CONCLUSION: In this article, we present a case in which OP was successfully treated with ozone injection.

Impact of ozone therapy on mouse liver mitochondrial function and antioxidant system.

Ozone therapy's efficacy might stem from the regulated and mild oxidative stress resulting from ozone's interactions with various biological elements. The present work aimed to characterize the hepatic mitochondrial response to ozone treatment and its relationship with the antioxidant system response. Two groups of mice were used: one control group and another injected intraperitoneally with an O3/O2 mixture (80 ml/kg) for 5 days. Mitochondrial respiration supported by different substrates was significantly inhibited, as well as complexes I and II/III, but not complex IV. The analysis of the electron transport chain complex activity showed significant inhibitions in complexes I and II/III but not in complex IV. These inhibitions can prevent mitochondrial reactive oxygen species (ROS) production. Additionally, there was a decline in glutathione content, unaccompanied by a rise in its oxidized form. The ozone-treated groups showed a significant increase in the activity of superoxide dismutase and glutathione peroxidase, while catalase and glutathione reductase experienced no significant alterations. Adenine nucleotides increased in the ozone group, but only the increase in adenosine diphosphate is significant, so the cell's energy charge is unaffected. This study shows that mitochondria may play a crucial role in ozone treatment. However, it also highlights the need for further studies to understand the molecular mechanism.

Oxygen-Ozone Therapy of Musculoskeletal Neck Pain: A Review.

Minimally invasive oxygen-ozone (O2-O3) therapy utilizing the biochemical effects of O2-O3 mixture is commonly used in the treatment of musculoskeletal pain. The literature dealing with O2-O3 therapy of spinal pain focuses mainly on the lumbosacral region. The aim of this review is to evaluate the efficacy of O2-O3 therapy in musculoskeletal pain in the neck region. The Medline (PubMed), SCOPUS, Web of Science, and Google Scholar databases were searched for clinical studies, using the free text terms: ozone, neck, cervical, spine, pain, disc, hernia, nucleolysis, paravertebral, treatment, and various combinations of them. In total, seven studies (two randomized controlled trials and five observational studies) were found. These studies dealt with the intradiscal or intramuscular paravertebral application of O2-O3 mixture in patients with myofascial pain syndrome, cervical disc hernias, and chronic neck pain. All these studies proved a significant decrease in neck pain (evaluated by Visual Analog Scale or Numerical Rating Scale), and most of them showed improvement in functional status (measured by Oswestry Disability Index or Neck Disability Index). In addition, other pain assessment scales and function and quality of life measures (DN4 questionnaire, pain pressure threshold, cervical lateral flexion range of motion, Japanese Orthopedic Association scale, 12- and 36-Item Short Form Surveys, modified MacNab criteria, and analgesic drug intake reduction) were used. Changes in these measurements also mostly supported the efficacy of O2-O3 treatment. No significant complications of the treatment were reported. The available evidence is sparse, but despite this, the O2-O3 treatment of musculoskeletal neck pain can be considered potentially beneficial and relatively safe.

Complementary and alternative therapies for managing postoperative pain after lower third molar surgery: a systematic review and network meta-analysis.

OBJECTIVE: The objective of this study was to evaluate the impact of complementary and alternative treatments on postoperative pain following lower third molar surgeries. METHODS: A comprehensive search of Electronic databases (Embase, MEDLINE via PubMed, and Cochrane Library) and grey literature was conducted up until May 2022. Randomized clinical trials investigating the effect of acupuncture, ozone therapy, laser (LLLT), drainage tube, kinesio-taping, ice therapy, and compressions on pain after LTM surgeries were included. The estimated mean differences (MD) for alternative therapies were pooled using the frequentist approach to random-model network meta-analysis NMA. RESULTS: Eighty-two papers were included in the qualitative analysis; 33 of them were included in the quantitative analyzes. NMA revealed that drainage tube and kinesio-taping were superior in controlling pain 24-hours postoperatively than no-treatment. At 48-hours follow-up, kinesio-taping and LLLT more effective than placebo and drainage tube; and kinesio-taping and LLLT were superior to no treatment. At 72 h postoperatively, ozone therapy was superior to placebo; and drainage tube, kinesio-taping, and LLLT were better than no treatment. At 7-days follow-up, ozone and LLLT were superior to placebo; and LLLT and kinesio-taping were superior to no treatment. The SUCRA-ranking placed drainage tube as top-ranking intervention at 48-hours (98.2%) and 72-hours (96%) follow-ups, and ozone (83.5%) at 7-days follow-up. CONCLUSION: The study findings suggest that these alternative and complementary therapies may be useful in reducing postoperative pain after LTM surgeries, and may offer advantages when combined to traditional pain management methods. CLINICAL RELEVANCE: Non-pharmacological therapies are gaining popularity among healthcare professionals and patients. This study found that some of these therapies, specifically kinesio-taping and drainage tube were effective in controlling postoperative pain after third molar surgeries. These findings have important implications for clinical practice, as they highlight the potential benefits of incorporating these therapies into postoperative pain management plans.

Ozone therapy improves early stages of osseointegration in ovariectomized rats.

OBJECTIVE: the aim of this study was to analyze the influence of ozone therapy (OZN) on peri-implant bone repair in critical bones by installing osseointegrated implants in the tibia of ovariectomized rats. METHODOLOGY: ovariectomy was performed on 30 Wistar rats, aged six months (Rattus novergicus), and, after 90 days, osseointegrated implants were installed in each tibial metaphysis. The study groups were divided into the animals that received intraperitoneal ozone at a concentration of 700 mcg/kg - OZ Group (n=15) - and a control group that received an intraperitoneal saline solution and, for this reason, was named the SAL group (n=15). The applications for both groups occurred during the immediate post-operative period on the 2nd, 4th, 6th, 8th, 10th, and 12th day post-surgery. At various stages (14, 42, and 60 days), the animals were euthanized, and tests were performed on their tibiae. These tests include histomorphometric and immunohistochemical analyses, computerized microtomography, sampling in light-cured resin for calcified sections, and confocal microscopy. The obtained data were then analyzed using One-way ANOVA and the Shapiro-Wilk, Kruskal-Wallis, and student t-tests (P<0.05). RESULTS: our findings indicate that the OZ group (3.26±0.20 mm) showed better cellular organization and bone neoformation at 14 days (SAL group, 0.90±1.42 mm) (P=0.001). Immunohistochemistry revealed that osteocalcin labeling was moderate in the OZ group and mild in the SAL group at 14 and 42 days post-surgery. The data from the analysis of calcified tissues (microtomography, histometric, and bone dynamism analysis) at 60 days showed no statistically significant differences between the groups (P=0.32). CONCLUSION: it was concluded that ozone therapy anticipated the initial phases of the peri-implant bone repair process.

Efficacy and safety of ozone therapy for knee osteoarthritis: an umbrella review of systematic reviews.

The objective of this study is to evaluate the effectiveness and safety of ozone therapy (OT) in the treatment of knee osteoarthritis (KOA), which is the most common form of the disease. We analysed systematic reviews (SRs) of randomised controlled trials (RCTs) using the "A MeaSurement Tool to Assess systematic Reviews" (AMSTAR2) instrument to evaluate their quality. We developed a narrative synthesis report with eight SRs (15 RCTs/3,685 patients) to summarise the findings. The AMSTAR2 analysis indicated that all reviews had critically low confidence ratings. Statistically significant effects in pain reduction using OT compared to placebo groups were reported in three SRs. OT was shown to be comparable to other therapies in one SR and not superior in the other five. Six SRs highlighted the need for additional RCTs with improved methodological quality to confirm the efficacy of OT for KOA. SRs found fewer consistent effects for improving joint function. Regarding safety, seven SRs reported a low prevalence of minor adverse events linked with OT. Finally, this umbrella review highlights the beneficial effects and safety of OT in the treatment of KOA, particularly in pain control. The low methodological quality of RCTs and SRs limits the possibility of drawing conclusions on the effectiveness of the procedure in comparison to other therapies. Ensure adequate compliance with guidelines such as Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and AMSTAR2 has the ability to improve the quality of SRs in this area.

Effectiveness of photo-ozone therapy against equine Pythium insidiosum.

Cutaneous pythiosis is a life-threatening infectious disease. Low-level laser therapy (LLLT) and ozone (O3) have been used individually in the treatment of infected wounds. The goals of the study were a) to characterize the antimicrobial action of the photo-ozone therapy (LLLT-O3) against equine Pythium insidiosum, and b) to assess the cytotoxic potential of the LLLT-O3 in keratinocytes. Specimens of pathogen were isolated from 10 horses. After culturing, 120 hyphae plugs were distributed among four groups (n=30 hyphae plugs/group): LLLT (laser irradiation for 160 sec;), O3 (exposition to O3 for 15 min;), LLLT-O3 (LLLT and O3 treatments in sequence) and control (untreated plugs). The hyphae growth was measured during the first 14 days post-treatment. Where there was an absence of hyphae growth, the plug was recultured for an additional 7 days. The cytotoxic potential of the treatments against HaCaT keratinocytes was assessed by colorimetric assays. The LLLT-O3 and O3 treatments inactivated, respectively, 92.3% (28/30) and 30% (9/30) of the samples. No growth was detected after 7 days reculture of inactivated hyphae plugs on new media. Hyphae growth was visualized in 100% of the control and LLLT hyphae plugs. The viability of HaCaT cells was not affected by the isolated treatments (LLLT and O3), while the LLLT-O3 showed slight cytotoxic effect (20%) when compared to the control group (P<0.05). Photo-ozone therapy inactivated equine P. insidiosum hyphae with minimal cytotoxicity in skin cells in vitro.

Selective excavation and ozone therapy: new frontier of mini-invasive caries treatment in MIH paediatric patients. A case report.

BACKGROUND: The term hypomineralisation of molars and incisors (MIH), introduced in 2001 by Weerheijm et al., describes a clinical state of hypomineralisation of permanent molars with frequent involvement of the incisors. MIH is considered a global dental problem with a prevalence ranging from 2.4% to 40.2% in the entire world paediatric population. The continuous increase in the prevalence of enamel anomalies, including MIH, indicates the need to define new intervention protocols based on the technological advances that are revolutionising paediatric dentistry. The use of ozone associated with the selective and minimally invasive excavation of the dental tissue combines the antibacterial properties of the gas with an ultra-conservative approach aimed at the maximum conservation of the dental tissue. The operative protocol described can be an important tool in the prevention and treatment of MIH. The aim of this work is to illustrate an operative clinical protocol based on the combined use of selective excavation and ozone for the treatment of carious lesions in paediatric patients with MIH.

Ozone therapy (O2-O3) alleviates the progression of early intervertebral disc degeneration via the inhibition of oxidative stress and the interception of the PI3K/Akt/NF-κB signaling pathway.

Intervertebral disc degeneration (IDD) stands for the most frequent cause of low back pain. Finding a cure for this disease is an important challenge as current conservative treatments and surgical interventions fail to bring a solution to this disease. Ozone therapy (O2-O3) has yielded outstanding outcomes in intervertebral disc pathology. The ozone's efficacy in the treatment of IDD remains unconfirmed. This study aimed to assess the effectiveness of intradiscal ozone injection on IDD induced in a rat. Effects of ozone therapy on the viability of nucleus pulposus cells were evaluated by CCK-8 assays. Macrophage immunoreactivity was detected by immunohistochemical, the expression of collagen type II was evaluated by western blot, and measurement of oxidative stress parameters was realized. Molecular docking studies were carried out in order to predict the interaction formed between O3 and the target enzymes, on the one hand, O3 with PI3K and, on the other hand, O3 with COX-2. IRM, X-ray, hematoxylin-eosin, and bleu alcian staining were realized to assess the therapeutic impacts of ozone in the puncture-induced rat model of IDD. In vivo, O3 ameliorated the IDD in the early stage of this disease. It was also displayed in molecular docking that O3 might bind to PI3K to suppress the PI3K/Akt/NF-κB signaling pathway. This study's results show that the O3 should be administered at the low grade of IDD and at an early stage because it cannot restore the advanced inflammatory alteration of the IVD. Our results corroborated also that O3 inhibits the progression of IDD via the PI3K/Akt/NF-κB signaling pathway, which supports O3 as an effective therapeutic option for treating IDD.

Ozone therapy effect in medication-related osteonecrosis of the jaw as prevention or treatment: microtomographic, confocal laser microscopy and histomorphometric analysis.

OBJECTIVE: This study aimed to evaluate the efficacy of ozone therapy in the preoperative (prevention) and/or postoperative (treatment) of MRONJ. MATERIAL AND METHODS: Forty male Wistar rats were caudally treated with zoledronic acid (ZOL) and to ozone therapy before extraction (prevention, POG), after extraction (treatment, TOG), or both (prevention and treatment, TPOG), and treated with saline (SAL). The animals received intramuscular fluorochrome (calcein and alizarin), and 28 days postoperatively, they were euthanized, and the tissues were subjected to microtomographic computed tomography (microCT), LASER confocal, and histomorphometric analyses. RESULTS: Micro-CT showed a higher bone volume fraction average in all groups than that in the ZOL group (P < 0.001), the ZOL group showed high porosity (P = 0.03), and trabecular separation was greater in the TOG group than in the POG group (P < 0.05). The mineral apposition rate of the POG group was high (20.46 ± 6.31) (P < 0.001), followed by the TOG group (20.32 ± 7.4). The TOG group presented the highest mean newly formed bone area (68.322 ± 25.296) compared with the ZOL group (P < 0.05), followed by the SAL group (66.039 ± 28.379) and ZOL groups (60.856 ± 28.425). CONCLUSIONS: Ozone therapy modulated alveolar bone repair in animals treated with ZOL, mainly after surgery trauma, leading to bone formation as healing tissue. CLINICAL RELEVANCE: Osteonecrosis has been a challenge in dentistry, and owing to the lack of a consensus regarding therapy, studies presenting new therapies are important, and ozone has been one of the therapies explored empirically.

Nociceptive and histomorphometric evaluation of the effects of ozone therapy on the rat masseter muscle in a carrageenan model of myofascial pain.

OBJECTIVE: This study evaluated the effects of intramuscular ozone therapy on nociception, inflammation, and tissue damage caused by the injection of carrageenan in the masseter muscle of rats. DESIGN: Rat masseter muscles were injected with saline or carrageenan. Seventy-seven adult male rats were divided into six groups: Sal, saline; Car, carrageenan; Ibup + Sal, ibuprofen and saline; Ibup + Car, ibuprofen and carrageenan; O3 + Sal, ozone and saline; and O3 + Car, ozone and carrageenan. The mixture of 5% ozone and 95% oxygen (20 µg/mL) was administered three times in the course of a week. Nociceptive responses in the masseter muscles were measured using a head withdrawal threshold, determined by an electronic von Frey anesthesiometer. The animals were euthanized one or eight days after the carrageenan injection, and the masseters were submitted to histological and histomorphometric analyses. RESULTS: Mechanical allodynia and inflammation levels were reduced in the Ibup + Car group compared to the other groups. Myonecrosis was similar among carrageenan-treated groups. Picrosirius red stained sections showed more collagen fibers and more regenerating myofibers in the O3 + Car group compared to the other groups. Eight days after carrageenan injection, the O3 + Car group showed neutrophils close to the regenerating myofibers. CONCLUSIONS: Intramuscular ozone therapy did not alleviate mechanical allodynia, and it did not protect the masseter muscle against the deleterious effects produced by carrageenan, probably due to the mode of administration of this therapeutic agent.

Use of oxygen-ozone therapy to improve the effectiveness of antibiotic treatment on infected arthroplasty: protocol for a superiority, open-label, multicentre, randomised, parallel trial.

INTRODUCTION: Surgical site infections still remain a major public health challenge and have become an increasing universal risk, especially for the implantation of orthopaedic devices.Unfortunately, the discovery and increasingly widespread use (especially the misuse) of antibiotics have led to the rapid appearance of antibiotic-resistant strains today; more and more infections are caused by microorganisms that fail to respond to conventional treatments.Oxygen-ozone therapy has been extensively used and studied for decades across various potential medical applications and has provided consistent effects with minimal side effects.This study aims to determine the superiority of oxygen-ozone therapy in combination with oral antibiotic therapy in patients with wound infections after an orthopaedic device implantation when compared with antibiotic therapy alone. METHODS AND ANALYSIS: This is an open-label, multicentre, randomised, parallel-group study that aims to assess the efficacy and safety of oxygen-ozone therapy in combination with oral antibiotic therapy to treat infections in patients (male or female aged ≥18 years) having undergone surgery for the implant of an orthopaedic device. Patients must have at least one (but no more than three) postoperative wounds in the site of surgery (ulcers, eschars and sores) and at least one symptom (pain, burning, redness and malodour) and at least one sign (erythema, local warmth, swelling and purulent secretion) of infection of at least moderate intensity (score ≥2) in the target lesion at the screening visit (patients with wounds without signs of localised infection or with undermining wounds will be excluded).Patients (n=186) will be recruited from five Italian hospitals and studied for 7 weeks. All will be assigned to one of the two treatment groups according to a web-based, centralised randomisation procedure and placed into either the (1) intervention: oxygen-ozone therapy 2-3 times a week for 6 weeks (for a maximum of 15 sessions) simultaneously with an appropriate oral antibiotic therapy prescribed at baseline or (2) control: oral antibiotic therapy prescribed at baseline.The primary outcome is the efficacy and superiority of the treatment (ozone and oral antibiotic therapies); secondary outcomes include the resolution of signs and symptoms, modifications in lesion size and the treatment's safety and tolerability. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the responsible Independent Ethics Committee (IEC) of COMITATO ETICO CAMPANIA NORD, located at 'Azienda Ospedaliera San Giuseppe Moscati di Avellino'.After completion of the study, the project coordinator will prepare a draft manuscript containing the final results of the study on the basis of the statistical analysis. The manuscript will be derived by the co-authors for comments, and after revision, it will be sent to a major scientific journal. Findings will be disseminated via online and print media, events and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04787575.