Efficacy of ozone injections for reducing musculoskeletal pain in comparison with corticosteroid injections: A systematic review and meta-analysis

Abstract

BACKGROUND:

Corticosteroid injections are frequently used in the short-term treatment of musculoskeletal pain, but their use is controversial as repeated exposures to corticosteroids can lead to deleterious effects on musculoskeletal tissue. Ozone injections have been proposed as a possible treatment for musculoskeletal pain; however, their effectiveness has not been compared with corticosteroids.

OBJECTIVE:

To evaluate the effectiveness of ozone injections for reducing pain in individuals with musculoskeletal pain in comparison with corticosteroid injections through a meta-analysis.

METHODS:

An online systematic search was performed using electronic databases up to September 2023. We searched for studies that compared corticosteroid injections with ozone injections in the treatment of musculoskeletal pain of diverse origins.

RESULTS:

Eleven studies were included comprising a total of 534 individuals. In the overall pooled analysis, a pain reduction in favor of corticosteroid injections was found in the short term ( $d=$ 0.31, 95% CI 0.01 to 0.60, p (z) 0.04, I2 $=$ 32%). In the medium term, no significant differences were found in reducing pain between groups ( $d=-$ 0.17, 95% CI $-$ 0.42 to 0.07, p (z) 0.15, I2 $=$ 0%).

CONCLUSIONS:

Our results suggest that corticosteroids injections are more effective in reducing musculoskeletal pain in the short term, but equally effective in the medium term when compared with ozone injections. Nonetheless, better-quality clinical trials are necessary to corroborate these results.

Keywords

Musculoskeletal diseases osteoarthritis tendinopathy nerve compression syndromes

1. Introduction

Musculoskeletal pain is defined as acute or chronic pain that affects bones, joints, muscles, ligaments, tendons and even nerves [1, 2, 3]. When pain lasts or it is recurrent during more than 3 months, it is considered chronic, and it is usually accompanied by alterations in the functional capacity and significant emotional alterations [1, 3, 4]. Currently, musculoskeletal pain represents one of the main causes of medical consultation in primary care [2, 4, 5]. It has been reported that the global prevalence ranges from 13 to 47% [5], increasing with age [2] and being more prevalent in women than in men [6]. The incidence of chronic musculoskeletal pain is estimated at 8.4% per year [5] worldwide. Additionally, musculoskeletal pain is found within the first 10 causes of disability [2] and it generates an unfavorable impact on economic participation and productivity [4]. Currently, the approach to skeletal muscle pain must have a multidisciplinary and multimodal approach, including non-pharmacological treatment, pharmacological treatment and interventional therapies [6].

Minimally invasive procedures can be part of a comprehensive and multimodal rehabilitation program, being very useful as part of the pharmacological treatment focused on pain control, which allows the patient to reduce the consumption of analgesics and start early specific rehabilitation programs based on exercise, which are the cornerstone of the rehabilitation of musculoskeletal conditions [7, 8, 9]. Minimally invasive procedures include injections with corticosteroids, hyaluronic acid, botulinum toxin, nerve blocks with local anesthetics or neurolytics, or procedures such as radiofrequency [6].

Corticosteroid injections (CI) are perhaps the most widely used minimally invasive interventional therapy in the treatment of musculoskeletal disorders such as knee and hip osteoarthritis [10, 11], rotator cuff tendinopathy [12, 13], epicondylitis [14], plantar fasciitis [15] and in nerve entrapments such as carpal tunnel syndrome [16, 17]. In knee osteoarthritis, CI represent a therapeutic option recommended by international guidelines [10, 18]; nonetheless, the CI beneficial effect has been reported to be limited to the short term in most studies [11, 12]; additionally, its use is controversial since repeated corticosteroid exposures can generate deleterious effects on tissues such as cartilage and tendon [19, 20].

Other therapeutic options have been proposed as a possible treatment for musculoskeletal pain, such as ozone injections (OI) [21, 22]. In patients with knee osteoarthritis (KOA), intra-articular OI are an effective intervention for reducing pain in the short term [23]; similarly, the efficacy of paravertebral OI for reducing low back pain has been reported [24]. It has been proposed that the main mechanism of action of ozone is related to anti-inflammatory effects and a decrease in local oxidative stress [22, 23, 24], having therapeutic effects similar to those of corticosteroids, but without generating the side effects that CI can have [26].

Up to today however, the scientific evidence reported in systematic reviews and meta-analyses on the efficacy of ozone for treating musculoskeletal pain have only been performed for knee osteoarthritis and chronic low back pain [23, 24]; therefore, it is necessary to establish and update other possible uses according to the current evidence on the efficacy of OI in the treatment of musculoskeletal pain in various locations.

The objective of this study was to evaluate the effectiveness of OI for reducing pain in individuals with secondary musculoskeletal pain (SMP) to specific pathologies, in comparison with CI, in order to determine if OI could represent a therapeutic alternative to CI.

2. Materials and methods

The methodology used in this work was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27], for the presentation of systematic review and meta-analysis.

The PICOS strategy used in the study is described below:

(P) Patients: Individuals with clinical and/or imaging diagnosis of secondary musculoskeletal pain to specific pathologies, who referred pain and alterations in functionality.

(I) Intervention: Ozone injections.

(O) Outcomes: Efficacy in reducing pain.

(S) Study design: Clinical trials and comparative observational studies.

2.1 Methods and search strategy

The articles of interest were identified in electronic databases, searching for publications up to September 2023. We used the National Library of Medicine (MEDLINE/PUBMED), Excerpta Medica Data Base (EMBASE); Cochrane Central Register of Controlled Trials (CENTRAL). Additionally, the search was completed using other online sources such as Scientific Electronic Library Online (SCIELO) and the Library of International Scientific Committee of Ozone Therapy (ISCO3) database. The search terminology included MESH terms, ENTRY terms, related terms and multiple combinations between them: [(ozone or ozone – therapy or ozone – injection) AND (musculoskeletal pain or musculoskeletal disease or musculoskeletal injuries) or (corticosteroids or corticoids or adrenal cortex hormones) or (shoulder or shoulder injuries or shoulder pain or shoulder impingement or rotator cuff injuries or rotator cuff tendinopathies) or (elbow or elbow joint or elbow injuries or tennis elbow or elbow tendinopathy or lateral epicondylitis) or (carpal joints or carpal injuries or hand injuries or carpal tunnel syndromes or entrapment neuropathy, carpal tunnel) or (hip or hip joint or acetabulofemoral joint or hip injuries or hip osteoarthritis or coxarthrosis) or (knee or knee joint or knee injuries or knee osteoarthritis) or (ankle joint or ankle injuries or ankle sprain or foot or foot joints or foot injuries) or (sacroiliac joint or sacroiliac injury or sacroiliac joint/pathology or sacroiliitis) or (cervical pain or cervical injuries or neck pain or cervicalgia) or (low back pain or low back injuries or lumbago or low back aches)]. The search comprised all the manuscripts reported in literature without language restrictions. The search formulas for each database are detailed in Supplement 1.

2.2 Type of studies and participants

This review included randomized clinical trials and controlled observational studies that used ozone injections as a therapeutic intervention for treating individuals with musculoskeletal pain of specified etiology and compared against corticosteroid injections. Basic experimental studies, clinical comments, one-case reports and review studies were excluded; clinical trials comparing ozone injections to other interventions different than corticosteroid injections were also excluded. The studies selected had to describe in detail the intervention performed, the forms of evaluation and the results.

The selected studies included individuals who met the following inclusion criteria:

Individuals with musculoskeletal pain secondary to specific pathologies such as osteoarthritis, tendinopathy, enthesopathy, peripheral nerve entrapment, bursitis or any other.

Individuals in whom a certain nosological diagnosis was established, through clinical and/or imaging evaluation and had pain and/or alterations in functionality as their main symptoms.

Adults of 18 years of age and older.

Both sexes.

The exclusion criteria were:

Studies that included individuals with primary musculoskeletal pain, such as fibromyalgia or nonspecific pain.

Studies that included patients without an established certainty nosological diagnosis.

2.3 Type of interventions

All selected studies met the following criteria for the type of intervention used in the experimental and control groups:

Individuals in the OI groups were treated with one or more sessions of injections with ozone, which consisted of intra-articular injections and/or peri-articular infiltrations with ozone alone or in combination with local anesthetics.

In the control groups, individuals were treated with one or more sessions of corticosteroid injections, which consisted of intra-articular injections and/or peri-articular infiltrations with corticosteroid alone or in combination with local anesthetics.

In the included studies, the interventions had to be performed via the same route and using the same technique in both groups.

The therapeutic procedures were performed with anatomical technique or under ultrasound guidance.

Co-interventions were allowed as long as they were uniform in all groups.

2.4 Evaluation of the risk of bias of the included studies

Two researchers independently assessed the risk of bias of each study included (PIAV and RGCA). Disagreements were resolved by consensus through the opinion of a third researcher (CATZ). The evaluation of clinical trials was based on the Cochrane Handbook for Systematic Reviews recommendations, version 5.1, which includes seven domains [28]. The risk of bias for each domain was classified as low, high or uncertain. The trial was considered low risk of bias only when all domains were rated as low risk of bias; if one or two domains were classified as high or uncertain risk of bias, the trial was considered uncertain (some concerns about the result); if three or more domains were classified as high or uncertain risk of bias, then the trial was considered high risk of bias.

The assessment of the risk of bias in non-randomized observational studies was performed using the ROBINS-I tool [29].

Additionally, for each study, the level of evidence for therapeutic studies was rated using the scale of the American Society of Surgeons; it classifies the level of evidence from I to V, according to the study design [30]. The quality of the evidence for the outcomes evaluated was determined with the GRADE system, taking into account criteria such as the study design, limitations in design and execution, inconsistency in results, presence of direct evidence, imprecision of results, publication bias and effect size [31].

2.5 Evaluation of eligibility and data extraction

Two researchers independently examined titles, abstracts and full texts; then they determined the eligibility of each study (PIAV and RGCA). Disagreements were resolved by consensus through the opinion of a third researcher (CATZ). For the eligible studies, data were extracted independently by the same researchers.

2.6 Outcomes

The efficacy of the interventions was evaluated in terms of the reduction in pain intensity, which was measured with pain assessment tools such as the visual analogue scale (VAS), numerical rating scale (NRS), the verbal rating scale (VRS) or with pain subscale scores of validated questionnaires specific for each pathology. Pain reduction was evaluated after having received the complete cycle of treatment, according to the time of follow-up in the short term ( $<$ 6 weeks) and medium term (8–12 weeks), which were the follow-up periods that were reported in all included studies.

The secondary outcomes were the characteristics of the treatment and the adverse effects, which were described according to the data provided in the included studies.

2.7 Statistical analysis and data synthesis

The meta-analysis was performed using Review Manager 5.4 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

For the quantitative analysis, the results were expressed in terms of means and standard deviations. When studies did not report their results in terms of mean and standard deviation, the RevMan Calculator was used to estimate them from the reported data; when this was not possible, the study was excluded from the quantitative analysis.

The efficacy of interventions was evaluated by analyzing the reduction of pain according to the follow-up time. The magnitude of the effect was measured with standardized mean difference (d) and 95% confidence intervals (95% CI). A random effects model for combining data was used, taking into account the clinical and statistical heterogeneity of the included studies. To evaluate the stability of the results in the meta-analysis, a sensitivity analysis was performed by excluding studies with the least statistical weight, eliminating the studies with a larger effect size in favor of OI and/or in favor of CI, or studies with high risk of bias.

The statistical heterogeneity was assessed in each meta-analysis using the I² and Chi² statistics, as well as Tau². Statistical heterogeneity was considered when I² was higher than 50% and either Tau² was bigger than zero or the P value was less than 0.10 in the Chi² test for heterogeneity.

The publication bias was evaluated graphically by Begg’s funnel plots and the asymmetry was considered as a significant presence of bias.

To evaluate the characteristics of the treatment and adverse effects, they were summarized in descriptive measures according to the data provided in the included studies.

3. Results

3.1 Search results

A total of 5237 citations were first identified and 3185 duplicates were excluded. Titles and abstracts of the remaining 2052 studies were read; then, 1829 studies of ozone therapy in non-musculoskeletal pathology, studies containing animal models, editorials, comments, environmental ozone studies and other unrelated were also excluded. Of the 223 remaining studies, 212 were excluded for the following reasons: review studies ( $n=$ 46), studies that compared OI with interventions other than CI ( $n=$ 64), duplicate ( $n=$ 1), studies that compared OI with CI but the injections were applied using a different route and/or technique between both groups ( $n=$ 16), uncontrolled observational studies ( $n=$ 54) and protocols ( $n=$ 31). Finally, eleven studies [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42] were eligible for inclusion in the qualitative analysis; In the quantitative analysis, eight clinical trials [33, 34, 35, 36, 37, 38, 41, 42] were included.

Figure 1.

Systematic review flow diagram.

The flowchart of the systematized search is shown in Fig. 1.

3.2 Study characteristics

Eleven studies [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42] that compared OI with CI in individuals with SMP were included.

Three studies evaluated the efficacy of OI versus CI in individuals with pain secondary to knee osteoarthritis [32, 33, 34], two studies in individuals with pain secondary to plantar fasciitis [35, 36], two study in patients with shoulder impingement [37, 41], two studies in patients with carpal tunnel syndrome [38, 39], one study in patients with pain secondary to lateral epicondylitis [40] and one study in patients with pain secondary to pes anserine bursitis [42].

Ten studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42] followed short-term results ( $<$ 6 weeks) and eleven studies [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42] followed medium term results (8 to 12 weeks), so only these follow-up periods were analyzed quantitatively.

Figure 2.

Summary assessment of the risk of bias of the included clinical trials.

In the analysis of risk of bias with the Cochrane tool, six clinical trials [35, 36, 37, 38, 41, 42] had unclear risk of bias and four studies had high risk of bias [32, 33, 34, 39] (Fig. 2). The observational study [40] included in the qualitative analysis showed low risk of bias in all items of ROBINS-I tool.

3.3 Demographics characteristics

This systematic review included 534 individuals diagnosed with SMP who met the inclusion criteria, 268 were treated with ozone injections and 268 were treated with corticosteroid injections. The average age in the groups treated with OI was 51.2 years while in CI groups was 50.2 years. The average duration of symptoms in the groups treated with OI was 11.47 months while in CI groups was 11.32 months.

3.4 Treatment characteristics

Most studies compared single OI session with single CI session [33, 34, 35, 36, 37, 38, 39, 42]. Two studies compared three OI sessions with a single CI session [32, 41] and one study compared six OI sessions with three CI sessions [40].

The groups treated with OI used an oxygen–ozone mixture at a concentration of 10 to 35 mcg/dl [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42], finding a statistical mode at 15 mcg/dl [34, 35, 41, 42]; a volume of oxygen–ozone mixture that varied from 2 to 20 ml per injection was used [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42], with mode of 10 ml [32, 34, 40]. In the groups treated with CI, methylprednisolone [32, 35, 36, 39], triamcinolone [33, 34, 37, 38, 42] or betamethasone [40, 41] were used.

In seven studies [34, 36, 37, 38, 39, 41, 42], the infiltration procedure was performed under ultrasound guidance; in the rest of the studies [32, 33, 35, 40] the landmarks technique was used.

In six studies included [32, 33, 34, 35, 39, 41], the participants were treated uniformly with an exercise program as a co-intervention. In two studies [33, 36] participants were treated uniformly with the use of orthoses.

Seven studies reported no secondary reactions or major adverse reactions in the treated groups [33, 34, 36, 37, 38, 40, 41].

Table 1
Characteristics of the interventions and results of study included

Author, year and level of study	Design, type and level of study	Ozone group	Corticosteroid group	Results	Adverse reactions and/or side effects
Mishra et-al., 2011 [32]. Level II	Randomized clinical trial, which included 46 patients diagnosed with KL grade $<$ II knee OA, divided into 2 groups.	23 patients treated with 3 IAI with 10 ml of ozone at 30 mcg/ml plus 2 ml of lidocaine, monthly frequency, performed with landmarks technique. Patients were recommended the application of local heat, knee exercises, paracetamol and lifestyle changes. Age: 42(4) Pain duration: $>$ 3 months	23 patients treated with an IAI of 40 mg of methylprednisolone plus 2 ml of lidocaine, performed with landmarks technique. Patients were recommended the application of local heat, knee exercises, paracetamol and lifestyle changes. Age: 42(4) Pain duration: $>$ 3 months	Number of patients and perception of pain in the pain subscale of the WOMAC scale. (Extreme-Severe- Moderate / Slight – Nil) Ozone Corticosteroid Baseline 23/0 23/0 12 weeks 5/18 9/14	Not reported.
Hashemi et al., 2017 [33]. Level II	Randomized clinical trial that included 61 patients diagnosed with KL grade II knee OA, divided into 2 treatment groups.	30 patients treated with an IAI of 5 ml of ozone at 35 mcg/ml. of concentration, performed with landmarks technique. Age: 56.7 (16.9) BMI: 22.6 (4.3) Pain duration: 14.5 (5.7) months	31 patients treated with an IAI of 50 mg (5 ml) of triamcinolone, performed with landmarks technique. Age: 54.8 (19.5) BMI: 21.4(3.8) Pain duration: 14.9 (7.3) months	Decrease in pain expressed as mean and standard deviation of numerical rating scale: Ozone Corticosteroid Baseline 6.8 (1.7) 6.9 (1.5) 4 weeks 1.7 (0.9) 1.9 (1.3) 12 weeks 2.3 (1.2) 4.6 (1.3) 24 weeks 2.5 (1.0) 4.9 (1.4)	Absence of adverse effects was reported in both groups.
Babaei-Ghazani et-al., 2018 [34]. Level II	Randomized clinical trial that included 62 patients diagnosed with KL grade I - III knee OA, divided into 2 treatment groups.	31 patients treated with an IAI of 10 ml of ozone at 15 mcg/ml. of concentration, performed under ultrasound guidance. Patients were instructed to perform quadriceps strengthening exercises during the course of the study. Age: 59.6 (10.2) BMI: 28.8 (2.4) Pain duration: 5.6 (1.3) months	31 patients treated with an IAI of 40 mg of triamcinolone, performed under ultrasound guidance. Patients were instructed to perform quadriceps strengthening exercises during the course of the study. Age: 56.2 (7.8) BMI: 29.2(4.5) Pain duration: 5.5 (1.5) months	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 77.3 (16.3) 80.9 (14.7) 1 week 55.0 (22.2) 48.5 (25.2) 4 weeks 53.9 (25.2) 48.5 (28.4) 12 weeks 53.1 (26.7) 62.6 (31.1)	Absence of adverse effects was reported in both groups.
Bahrami et-al., 2019 [35]. Level II	Randomized clinical trial that included 44 patients diagnosed with plantar fasciitis, divided into 2 treatment groups.	21 patients treated with a local injection of 3 ml of ozone at 15 mcg/ml. of concentration plus 1 ml of lidocaine, performed with landmarks technique. All the participants were instructed to carry out a program of stretching exercises for the gastrosoleus muscles, application of cryotherapy and use of a plantar orthosis. Age: 47.7 (9.7) Pain duration: 9.7 (4.9) months BMI: 28.6 (3.1)	23 patients treated with a local injection of 40 mg of methylprednisolone plus 1 ml of lidocaine, performed with landmarks technique. All the participants were instructed to carry out a program of stretching exercises for the gastrosoleus muscles, application of cryotherapy and use of a plantar orthosis. Age: 47.5 (8.7) Pain duration: 10.2 (7.5) months BMI: 28.5 (3.4)	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 7.4(1.5) 7.30 (1.4) 4 weeks 4.4 (1.1) 3.3 (1.9) 12 weeks 3.1 (1.5) 3.0 (1.1)	Not reported.

Table 1, continued
Author, year and level of study	Design, type and level of study	Ozone group	Corticosteroid group	Results	Adverse reactions and/or side effects
Babaei-Ghazani et-al., 2019a [36]. Level II	Randomized clinical trial that included 30 patients diagnosed with plantar fasciitis, divided into 2 treatment groups.	15 patients treated with a local injection of 2 ml of ozone at 20 mcg/ml. of concentration, performed under ultrasound guidance. Participants were advised to perform stretching exercises for the plantar fasciae and posterior leg muscles. Age: 48.4 (8.8) Pain duration: 7.8 (6.4) months BMI: 28.8(2.4)	15 patients treated with a local injection of 40 mg of methylprednisolone, performed under ultrasound guidance. Participants were advised to perform stretching exercises for the plantar fasciae and posterior leg muscles. Age: 44.1 (9.1) Pain duration: 11.9 (14.4) months BMI: 29.2 (4.5)	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 58.0 (15.2) 50.0 (10) 2 weeks 44.3 (18.4) 26.0(15.4) 12 weeks 18.6 (11.2) 26.0 (19.5)	Absence of adverse effects was reported in both groups.
Babaei-Ghazani et-al., 2019b [37]. Level II	Randomized clinical trial that included 30 patients diagnosed with Shoulder impingement, divided into 2 treatment groups.	15 patients treated with a subacromial injection of 8 ml of ozone at 12 mcg/ml. of concentration, performed under ultrasound guidance. All participants were instructed to carry out an exercise program at home. Age: 59.4 (10.31) Pain duration: 10.8 (9.5)	15 patients treated with a subacromial injection of 40 mg of triamcinolone, performed under ultrasound guidance. All participants were instructed to carry out an exercise program at home. Age: 55.8 (14.7) Pain duration: 7.6 (4.8)	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 7.7 (1.1) 7.4 (1.4) 2 weeks 5.7(1.1) 2.6 (1.4) 8 weeks 4.8(1.5) 2.9 (1.7)	Absence of adverse effects was reported in both groups.
Forogh et-al., 2021 [38]. Level II	Randomized clinical trial that included 40 patients with carpal tunnel syndrome, divided into 2 treatment groups.	20 patients treated with an intracarpal injection of 3 ml of ozone at 10 mcg/ml. of concentration plus 1 ml of lidocaine, performed under ultrasound guidance. All patients were recommended to wear a carpal splint for 6 weeks after the injection. Age: 54.7 (6.6) Pain duration: 9.1 (5.1) months.	20 patients treated with an intracarpal injection of 40 mg of triamcinolone plus 1 ml. of lidocaine, performed under ultrasound guidance. All patients were recommended to use a carpal splint for 6 weeks after the injection. Age: 53.6 (9.2) Pain duration: 10.8 (8.6) months.	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 5.9 (2.2) 6.8 (2.0) 6 weeks 3.5 (2.5) 3.2 (2.3) 12 weeks 3.7(2.6) 3.0 (2.2)	Absence of adverse effects was reported in both groups.
Elawamy et-al., 2021 [39]. Level II	Randomized clinical trial that included 50 patients with systemic sclerosis and carpal tunnel syndrome, divided into 2 treatment groups.	25 patients treated with an intra-carpal injection of 20 ml of ozone at 25 mcg/ml. of concentration, performed under ultrasound guidance. Age: 41.4 (12.7) Pain duration: 7.8 (6.4) months	25 patients treated with an intra-carpal injection of 40 mg methylprednisolone $+$ 40 mg lidocaine, performed under ultrasound guidance. Age: 38 (12.5) Pain duration: 11.9 (14.4) months	Decrease in pain expressed as median and interquartile range of the visual analog scale: Ozone Corticosteroid Baseline 80.0 (11.0) 77 (8.0) 4 weeks 50.0 (12.5) 50 (20.0) 12 weeks 42.0 (12.0) 60.0 (20.0) 24 weeks 35.0 (12.0) 60.0 (20.0)	Not reported.

Table 1, continued
Author, year and level of study	Design, type and level of study	Ozone group	Corticosteroid group	Results	Adverse reactions and/or side effects
Ulusoy et-al., 2020 [40]. Level III	Observational study that included 80 patients diagnosed with epicondylitis, divided into 2 treatment groups.	42 patients treated with 6–8 injections of 10 ml of ozone at 10 mcg/ml. concentration, at intervals of every 3 days, performed with landmarks technique. Age: 45.1 (8.1) Pain duration: 25.1 (12.8) months	38 patients treated with three injections of betamethasone dipropionate (6.43 mg) $+$ betamethasone sodium phosphate (2.63 mg), at weekly intervals, performed with landmarks technique. Age: 46.4 (6.8) months Pain duration: 23.6 (12.3)	Number of patients and perception of pain during activity evaluated with the modified Verhaar scale. (Fair-Poor/Excellent-Good). Ozone Corticosteroid Baseline 41 /1 38/0 Immediate 10/32 10/28 12 weeks 4/38 19/19 24 weeks 4/38 23/15 36 weeks 6/36 35 / 3	Absence of adverse effects was reported in both groups.
Atar et-al., 2023 [41]. Level II	Randomized clinical trial that included 44 patients diagnosed with chronic rotator cuff tendinopathy divided into 2 treatment groups.	22 patients treated with three subacromial injections (1 session/week) of 5 ml of ozone at 15 mcg/ml. of concentration, performed under ultrasound guidance. All participants were instructed to carry out an exercise program daily. Age: 48.2 (10.3) Pain duration: 21.3(25.6) months.	22 patients treated with a subacromial injection of a mixture of 1 mL corticosteroid (betamethasone 3 mg/mL) and 1 mL lidocaine (20 mg), performed under ultrasound guidance. All participants were instructed to carry out an exercise program daily. Age: 50.1 (12.7) Pain duration: 13.8 (23.2) months.	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Baseline 75.5(17.0) 65.2(15.8) 4 weeks 36.5(22.0) 37.3(21.7) 12 weeks 31.7 (26.4) 35.0 (25.5)	Absence of adverse effects was reported in both groups.
Babaei-Ghazani et-al., 2023 [42]. Level II	Randomized clinical trial that included 72 patients diagnosed with pes anserine bursitis, divided into 3 treatment groups.	24 patients treated with a local injection of 5 ml of ozone at 15 mcg/ml. of concentration, performed under ultrasound guidance. Age: 60.0(8.3) BMI: 29.6(2.6)	25 patients treated with a local injection of 40 mg of triamcinolone, performed under ultrasound guidance. Age: 64.2(10.0) BMI 31.3 (7.8) 23 patients treated with a local injection of 2ml of dextrose at 20%, performed under ultrasound guidance. Age: 59.3(8.9) BMI: 32.6(6.9)	Decrease in pain expressed as mean and standard deviation of the visual analog scale: Ozone Corticosteroid Dextrose Baseline 8.0(1.3) 8.0 (1.5) 7.6(1.3) 2 weeks 4.8(2.5) 4.5(2.7) 7.2(1.7) 8 weeks 3.8(2.5) 5.0(2.5) 3.5(1.8)	Not reported.

OA: Knee Osteoarthritis; IAI: Intra – articular injection; WOMAC: Osteoarthritis Index of Eastern Ontario and McMaster University; BMI: body mass index; KL: Kellgren-Lawrence.

The characteristics of the interventions and results of each study included are reported in Table 1.

3.5 Quantitative analysis for overall pain reduction

To analyze the efficacy of OI in the reduction of pain according to the time of evolution, a meta-analysis was performed including eight studies [33, 34, 35, 36, 37, 38, 41, 42] in the short and medium term of follow-up.

Figure 3.

Forest plot for pain reduction in the short term for musculoskeletal pain of various locations: A) Overall analysis; B) Sensitivity analysis.

In the pooled analysis, a statistically significant difference was observed in pain reduction in favor of CI groups, in the short term ( $d=$ 0.46, 95% CI 0.01 to 0.90, p (z) 0.04, I2 $=$ 76%) (Fig. 3A). Heterogeneity was found in the short term and a sensitivity analysis was performed by eliminating the study with a larger effect size in favor of CI [37] and the study with a larger effect size in favor of OI and high risk of bias [33]; the heterogeneity was eliminated and the statistical significance remained in favor of the CI group in the short term (d $=$ 0.31, 95% CI 0.01 to 0.60, p (z) 0.04, I2 $=$ 32%) (Fig. 3B).

The pooled analysis in the medium-term evaluation showed no statistically significant differences in pain reduction between those treated with OI and CI ( $d=-$ 0.23, 95% CI – 0.76 to 0.31, p (z) 0.84, I2 $=$ 41%) (Fig. 4A). Heterogeneity was found in the medium term results and a sensitivity analysis was performed by eliminating the study with a larger effect size in favor of CI [37] and the study with a larger effect size in favor of OI and high risk of bias [33]; the heterogeneity was eliminated and the results remained without statistical difference between groups ( $d=-$ 0.17, 95% CI $-$ 0.42 to 0.07, p (z) 0.15 I2 $=$ 0%) (Fig. 4B).

When evaluating publication bias, no asymmetry was found in the Begg’s funnel plots that evaluated short and medium-terms pain reduction.

4. Discussion

The aim of the present systematic review was to evaluate the effectiveness of OI for reducing pain in individuals with SMP in comparison with CI, in order to determine if OI could represent a therapeutic alternative to CI.

Some literature reviews [21, 22] have described the benefits of OI in patients with musculoskeletal pain, however, no analyses of the evidence were performed. In our qualitative analysis, eleven studies that directly compared OI to CI in individuals with SMP were included, of which eight clinical trials [33, 34, 35, 36, 37, 38, 41, 42] were quantitatively analyzed. In the pooled analysis by follow-up period, a statistically significant difference in the short-term pain reduction was found in favor of the CI in individuals with SMP (Fig. 3). In the medium term, the pooled analysis indicated that there was no statistically significant difference between groups in the reduction of pain (Fig. 4). Seven studies reported no secondary reactions or major adverse reactions in individuals treated with OI [33, 34, 36, 37, 38, 40, 41].

Next, we analyzed these results and associated them with the proposed mechanisms of action for ozone injections in the various musculoskeletal tissues.

Figure 4.

Forest plot for pain reduction in the medium term for musculoskeletal pain of various locations: A) Overall analysis; B) Sensitivity analysis.

Three studies evaluated the efficacy of intra - articular injections with ozone against corticosteroids in individuals with pain secondary to joint pathology, specifically in knee osteoarthritis [32, 33, 34]. Intra-articular injections with corticosteroids are recommended by international guidelines for the treatment of knee osteoarthritis, generating a short-term reduction in pain [10, 18]. In relation to OI, others review studies have reported their efficacy for reducing pain in the short term in patients with knee osteoarthritis during 1 to 3 months in comparison to non-invasive treatments, placebo injections or intra-articular injections with hyaluronic acid; however, no study directly compared OI versus CI [23, 43, 44]. In the individual quantitative analysis, we found that there were no statistically significant differences in pain reduction when comparing OI versus CI in the short and medium terms, in none of the included studies [33, 34].

The mechanisms of action of ozone on articular cartilage have been studied at a preclinical and clinical level. Animal model studies have reported that intra–articular injections with ozone induced a decrease in the levels of TNF- $\alpha$ , IL-1 $\beta$ and IL-6, as well as the regulation of intra-articular oxidative stress without generating cartilage toxicity, in rats with rheumatoid arthritis model [45, 46]. In a model of osteoarthritis in rabbits, it was found that intra-articular ozone injections decreased the expression of matrix metalloproteinase-1 (MMP-1) and bone morphogenetic protein-2 (BMP-2) when compared to controls, which was an indicator of decreased cartilage degradation [47]. A recent study [48] reported that intra-articular injections with ozone decreased the volumetric density of the joint injury in a model of cartilage injury induced in rats, delaying joint degeneration. These results have been reproduced in humans; Hashemi et al. [33] reported a decrease in serum IL-1B and TNF- $\alpha$ levels in patients with osteoarthritis of the knee treated with intra-articular ozone injections or intra-articular corticosteroid injections, without differences between groups at one month of follow-up, and with a longer effect (three months follow-up) in the ozone group. Similarly, Fernandez-Cuadros et al. [49] showed that intra-articular injections with ozone, significantly decreased serum concentrations of IL-6 in patients with knee osteoarthritis. Calunga et al. [50] reported a decreased oxidative stress and re-establishment of intra-articular redox balance in patients with knee osteoarthritis who were treated with intra-articular ozone injections. Fernandez-Cuadros et al. [49] reported that intra-articular injections with ozone slightly increased serum concentration of IGF-1 in patients with knee osteoarthritis without obesity or diabetes, which could be a biomarker of the anabolic effects induced by ozone. Apparently, in humans, the reduction of oxidative stress and inflammation markers such as TNF $\alpha$ and IL-1 $\beta$ generated by the ozone treatment could be related to an induction of the phosphorylation and activation of the nuclear erythroid factor 2 (Nrf2) [51]. The mechanism of action of corticosteroid injections is well known, decreasing proinflammatory effects of the arachidonic acid by acting directly on nuclear steroid receptors that alter mRNA and protein synthesis, leading to reduced transient levels of cytokines, enzymes and phospholipase A2 [11, 52, 53]. The inhibition of growth factors by corticosteroids has also been reported [53], generating a blocking or slowing effect on tissue repair [54]. Apparently, both therapies exert their therapeutic effect through a mechanism of action based on anti-inflammatory effects [33, 49, 52, 53]; ozone however, has additional mechanisms of action: the modulation of oxidative stress [50] and the increase of IGF-1 release [49], which appears to have the advantage of not inhibiting the release of growth factors and not blocking the process of tissue repair, opposite to what happens with the use of corticosteroids [54]. Although intra-articular injections with corticosteroids reduce pain in the short term in individuals with knee osteoarthritis [11], the repeated application could have deleterious effects on the cartilage [55, 56]. It seems that both interventions generate a reduction of proinflammatory cytokines [33, 49, 52, 53] which could explain the symptomatic improvement observed in the short term. As an additional effect of OI, there is the reduction of joint oxidative stress [50] and its apparent anticatabolic effect on the cartilage [49], which would represent an additional effect to that generated by CI. The results found and the proposed mechanisms of action, indicate that OI could represent a potential alternative to CI, for the reduction of pain in the short and medium terms in individuals with knee osteoarthritis, especially when corticosteroids are contraindicated; nonetheless, some studies have proposed a synergistic effect using both therapies [57, 58].

In our qualitative analysis on the other hand, five studies were included, in which tendon pathologies were treated such as plantar fasciitis [35, 36], rotator cuff tendinopathy [37, 41] and epicondylitis [40], of which four were analyzed quantitatively [35, 36, 37, 41].

In studies of pain secondary to plantar fasciitis, CI was more effective in reducing pain in the short term than non-pharmacological therapies such as the use of orthoses or physical therapy [15] and without a statistically significant difference in the short and medium terms when compared with shock wave therapy or injections with platelet-rich plasma or local anesthetics [15]. In the individual quantitative analysis, CI was more effective in reducing pain in the short term, but without statistically significant differences in the medium term, in both included studies [35, 36].

In pain secondary to rotator cuff tendinopathy, CI was an effective intervention in reducing pain in the short term [12]. In the individual quantitative analysis, the results appear to be dose dependent. Babaei-Ghazani et al. [37] applied a single subacromial injection of ozone compared to a single subacromial injection of corticosteroids and the result was in favor of corticosteroids in the short and medium terms; however, the study by Atar et-al [41] applied three subacromial injections of ozone and compared them with a single subacromial injection of corticosteroids and found no differences between interventions in the short and medium terms. This coincides with other studies that have reported good efficacy of ozone injections to reduce pain in patients with shoulder tendon pathology when multiple ozone injections have been used [59, 60]. This suggests that a single OI is not enough to equal the beneficial effects of CI in the treatment of shoulder tendon pathology; several sessions of OI may be necessary to increase its beneficial effect [61].

In pain secondary to epicondylitis, we were able to observe a similar therapeutic response. Corticosteroid injections have been an effective intervention for reducing pain in the short term in patients with epicondylitis when compared with platelet-rich plasma [14] or shock wave therapy [62]. Likewise, OI has been compared with shock wave therapy [63, 64], and no statistically significant differences in pain reduction in the short and medium term were reported. In our qualitative analysis we included only one study that compared OI versus CI in epicondylitis [40], unfortunately it did not meet the criteria to be analyzed quantitatively; nonetheless, their results indicated that when comparing six sessions of OI with 3 sessions of CI, there were no statistically significant differences between interventions in the short term, but in the medium term the effect was in favor of OI. On the contrary, a study published in abstract form [65] reported that a single session of OI was compared with a single session of CI in patients with recalcitrant epicondylitis and they observed a significant pain reduction and function improvement in both groups, but with a difference in favor of CI in the short and medium terms. Once again, these data suggest that perhaps several sessions of OI are necessary to achieve favorable effects that are comparable to a single session of CI in tendon pathologies.

Corticosteroid injections are a frequent intervention in the treatment of tendinopathies of various locations, but up until now their efficacy has only been demonstrated in the short term [12, 14, 15, 62]. The mechanism of action has already been discussed here, mainly involving anti-inflammatory effects [52, 53]; in tendinopathies however, the inflammatory process is not always underlying the pathophysiological mechanism [66, 67], which explains why CI only works in the short term. Corticosteroid injections not only inhibit the release of growth factors [54], they also have possible deleterious effects on the tendon after a repeated use. The deleterious effects include a decrease in extracellular matrix synthesis (especially in type I collagen), collagen disorganization, cell necrosis and apoptosis, calcifications [13, 68, 70, 71] that could end in tissue atrophy and tendon rupture [72, 73], as well as the systemic side effects [74]; therefore, it was necessary to determine whether the use of corticosteroid injections is a useful treatment for tendinopathies. In the case of OI, the mechanisms of action are also based on the reduction of the pro-inflammatory state, plus decreasing the local oxidative stress [33, 45, 46, 49]. An experimental animal model study, reported that ozone injections applied to injured tendons in rabbits significantly increased cellularity, vascularity and collagenization of the tendon, with a greater number and better organization of collagen fibers when compared to control groups that did not receive injections with ozone [75]. This suggests that OI stimulate anti-degenerative and trophic mechanisms of the tendon, which could be an advantage when compared with corticosteroids and could explain why in order to achieve beneficial effects several applications are required. Perhaps OI represents a potential alternative to CI for the reduction of pain in the medium term in individuals with tendinopathy, especially when corticosteroids are contraindicated, requiring several sessions to achieve the beneficial effects.

Two studies [38, 39] that compared OI with CI in individuals with pain secondary to carpal tunnel syndrome were included in the qualitative analysis. Various studies have reported that CI are an effective intervention for the management of carpal tunnel syndrome [16, 17]; the duration of their effect however, is limited to 4 weeks and there is no evidence of their long-term beneficial effect [16]. In the individual quantitative analysis, we found that there were no differences between interventions in the short and medium follow-up term in pain reduction, although only one study reported sufficient data to be included and this did not allow us to draw conclusions. Preclinical studies have studied the effect of ozone on neural tissue. Basic studies performed in animal models have reported that perineural applications of ozone at 10 to 80 mcg/ml do not cause damage to the structure or function of the sciatic nerve in rats [76], reducing oxidative stress and restoring balance nerve redox [77], as well as favoring the myelination process [76] and nerve repair without increasing fibrous tissue [78]. According to the results found and the reported mechanisms of action, OI could have favorable effects in individuals with carpal tunnel syndrome when compared with CI, as both interventions have an anti-inflammatory effect, but ozone provides additional benefits based on a reduction in local oxidative stress and favors nerve recovery.

According to the results found in our meta-analysis and the approaches made around the mechanisms of action of both interventions, we can highlight the following observations:

The CI are more effective than OI for reducing SMP in the short term. These results coincide with other meta-analyses that have reported beneficial effects of CI for SMP reduction in the short term [11, 12, 14, 15, 16]; it is necessary to take into account that this benefit is lost in the medium and long terms, and CI can generate adverse effects at local level of the treated tissue and at systemic level when repeated exposures are made [19, 55, 56].

In the medium term, no differences were found in the efficacy for the reduction of SMP, between CI and OI. Considering the contraindications and possible adverse effects of CI, perhaps in these cases OI could be a treatment option to CI.

Apparently, the mechanisms of action of OI are similar regardless of the treated tissue. The OI appear to have a modulating effect on inflammation [33, 49], but it also generates a reduction of local oxidative stress [48, 50, 76] with anti-degenerative [47, 48, 78] and even trophic effects [49, 69, 75, 78] on the treated tissues. These suggest that pain control mechanisms are not exclusively anti-inflammatory, but rather antioxidant, which can have a desensitizing and antidegenerative effect on the tissues treated; both mechanisms confer some advantages over CI alone, and perhaps OI is more compatible with other emerging regenerative therapies such as prolotherapy with dextrose [79], platelet-rich plasma [80] or hyaluronic acid [81]. CI may not be as compatible with these therapies, as they involve within their mechanisms of action, a reduction in the release of growth factors and a possible deleterious effect on the tissue [19, 54, 55, 56].

Apparently, there are differences in the number of sessions necessary to achieve a beneficial effect, when comparing CI with OI. Some studies suggest that a single session of OI is not enough to equate the effects of a single session of CI in reducing SMP of tendon origin [37, 40, 41, 61, 65]. A priori, this represents a possible disadvantage for OI. Maybe a single OI is not an alternative treatment to CI in the short term; nonetheless, the possibility of repeated OI sessions in the medium term without side effects, could make it an option in the treatment of recalcitrant pain, especially for its desensitizing and antidegenerative effect on the tissues treated; unlike CI, which due to its side effects, is not convenient to use in multiple sessions.

Both therapeutic strategies could take place in the comprehensive and multimodal rehabilitation program for musculoskeletal pain, depending on various factors such as the type of musculoskeletal pathology, the time of evolution and the comorbidities and particularities of the individual. OI is a therapeutic strategy with anti-inflammatory and antioxidant effects, that appears to be an option to CI for the reduction of musculoskeletal pain in the medium term and perhaps can be integrated in the context of multimodal rehabilitation as a strategy focused on pain control, which will allow the patient to begin their exercise-based rehabilitation program more quickly [6, 7, 8, 9].

The results of our meta-analysis indicate that in individuals with SMP, CI are more effective for pain reduction in the short term (GRADE moderate $\oplus\oplus\oplus\ominus$ ). In the medium term, OI have similar efficacy to CI for reducing pain (GRADE moderate $\oplus\oplus\oplus\ominus$ ) (Supplement 3).

However, our results should be taken with reservations, given some limitations: Eight studies were included in the quantitative analysis, where OI was compared with CI, resulting in 360 individuals analyzed. Without a doubt, more quality clinical trials that directly compare OI versus IC in musculoskeletal pathologies are necessary. Perhaps our study will serve as a catalyst to increase scientific production on this topic and achieve a greater volume of publications that allows us to corroborate these results.

Another limitation is that the results are based on the combined analysis of several pathologies of musculoskeletal origin, which makes the sample heterogeneous and does not allow specific conclusions to be drawn. Unfortunately, a maximum of two studies were found per pathology, which did not allow a specific quantitative analysis to be performed. However, when analyzing the mechanisms of action of ozone injections, we can observe that they are very similar in all tissues and that expected effect seems to have the same statistical behavior when comparing the global analysis and the individual analysis of each study.

Of the studies included in the quantitative analysis, six of them had unclear risk of bias and two had high risk of bias. In the sensitivity analysis, only one study had a high risk of bias. Despite this, in the GRADE analysis, the quality of the evidence was moderate for pain reduction in the short and medium terms.

Another limitation is that the majority of the included studies only had short and medium terms follow-up. Perhaps long-term follow-up studies could give us the opportunity to know if OI has a beneficial effect of delayed onset compared with CI, as happens when comparing CI with other interventions such as hyaluronic acid or platelet-rich plasma.

Not all studies used ultrasound guidance to perform infiltration, perhaps this is another limitation. Of the eight studies included in the quantitative analysis, in six of them the infiltration was performed under ultrasound guidance and in the sensitivity analysis almost all of the included studies were performed under ultrasound guidance. The use of ultrasound guidance for the application of ozone injections in the treatment of musculoskeletal pathologies can have certain advantages: Pre-procedural ultrasound evaluation allows identifying the anatomical structure to be treated and choosing the most appropriate range of needle length; The real-time evaluation allows you to follow the procedure step by step, which positively influences the safety and precision of the treatment; the post – procedure evaluation allows confirming the optimal distribution of ozone in the injected tissue; All this gives us the opportunity to optimize results [82]. However, the use of ultrasound guidance requires adequate training and greater resources.

5. Conclusions

In this systematic review and meta-analysis, we found that CI were more effective than OI in short-term pain reduction in individuals with SMP; in the medium term, no differences were found in pain reduction between CI and OI in individuals with SMP. OI appears to be a safe intervention that does not cause adverse reactions or major side effects. OI represents a therapeutic intervention that seems effective in reducing SMP in the medium term and a potential option to the use of corticosteroids, especially in patients where the application of corticosteroids implies a greater risk of adverse effects. However, the limitations of our study reduce the evidence provided and it is not possible to draw definitive conclusions. More clinical trials with good methodological quality, low risk of bias and long-term follow-ups are necessary to corroborate these results.

Author contributions

Conceptualization and design: PIAV, MNG, DRG; data collection: PIAV, RGCA, CATZ, MANAM; analysis and interpretation of results: PIAV, MNG, DRG, CATZ; draft manuscript preparation: PIAV, MNG, DRG, RGCA, CATZ, MANAM. All authors reviewed the results and approved the final version of the manuscript.

Data availability statement

Data is available from the corresponding author upon request.

Ethical approval

Not applicable.

Funding

Not applicable.

Informed consent

Not applicable.

Supplementary data

The supplementary files are available to download from https://dx-doi-org.web.bisu.edu.cn/10.3233/BMR-230173.

Footnotes

Acknowledgments

The authors are grateful to Dr. Adalberto Loyola Sánchez for the access to research-related information.

Conflict of interest

The authors declare that they have no conflict of interest.

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Efficacy of ozone injections for reducing musculoskeletal pain in comparison with corticosteroid injections: A systematic review and meta-analysis

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Methods and search strategy

2.2 Type of studies and participants

2.3 Type of interventions

2.4 Evaluation of the risk of bias of the included studies

2.5 Evaluation of eligibility and data extraction

2.6 Outcomes

2.7 Statistical analysis and data synthesis

3. Results

3.1 Search results

3.4 Treatment characteristics

Table 1 Characteristics of the interventions and results of study included

Author contributions

Data availability statement

Ethical approval

Funding

Informed consent

Supplementary data

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Characteristics of the interventions and results of study included