Introduction

The low back pain is an extremely frequent health problem, with an incidence of 36% and with one-year recurrence of 50% [1]. The prevalence in one year can reach up to 56% and the prevalence during life is 84% [1,2]. The etiology of low back pain is multifactorial and it is classified based on the mechanism of injury, etiological diversity, time of evolution and degree of radicular involvement [3]. Although there are various treatment modalities for this pathology, there is no standard or specific treatment for it. A conservative treatment represents the first line of action in individuals with chronic low back pain [4,5]. On the other hand, multidisciplinary rehabilitation programs [6] including exercise [7,8] and some physical therapeutic modalities such as heat, electrotherapy and laser represent the main non-invasive treatments [5]. Likewise, current pharmacological treatment includes the use of non-steroidal anti-inflammatories in short cycles to control acute and subacute pain [5,9], the use of muscle relaxants in the presence of spasms [5] and as a second line with certain restrictions, the use of opioids and neuromodulators [6,10,11].

When a non-invasive treatment is ineffective, evidencebased guidelines recommend other intervention techniques such as epidural steroid infiltration [12,13]; that is the most effective intervention in reducing pain in the short-term in individuals with low back pain secondary to herniated disc [14]. Nevertheless, the epidural steroid infiltration in individuals with radiculopathy or lumbar stenosis is still controversial [15]. Other procedures for treating low back pain include: Facet infiltrations [12,13,16], botulinum toxin injection into lumbar paravertebral muscles [17], local anesthetics infiltration [18], infiltration of ligaments and facets with hypertonic dextrose (prolotherapy) [19] and infiltration of an oxygen-ozone mixture [20] with little evidence of its effectiveness.

The ozone application has been used in the treatment of low back pain secondary to herniated disc with or without sciatic irradiation [21,22] and other pathologies such as degenerative spinal disease [23], spinal stenosis [24] and failed surgery syndrome [25]. Ozone applications are performed in various ways: intradiscal (most used and most effective) [26-28], intraforaminal [29,30] and infiltrations into lumbar paravertebral muscles [20,21]. However, due to the little and controversial scientific evidence of the use of ozone infiltration in paravertebral muscles in individuals with low back pain, it has been classified as a complementary therapeutic intervention. Therefore, we conducted a systematic review with the objective of analyzing the efficacy, application characteristics and side effects and / or adverse reactions of intramuscular infiltrations with ozone in lumbar paravertebral muscles in individuals with acute or chronic low back pain, with or without radicular pain.

Methods

For this study, we followed the PRISMA Reporting Guidelines for Systematic Review and Meta-analysis [31].

Study Selection

This review included controlled clinical trials and observational studies (cases - controls, case series) where the therapeutic intervention was Intramuscular Infiltrations of Ozone in Lumbar Paravertebral Muscles (IIOLPM), as a treatment for individuals with low back pain with or without sciatica data. We excluded animal model studies, reviews, case reports, as well as studies where the treatment included IIOLPM and a concomitant treatment with other forms of ozone application (intradiscal, intraforaminal infiltrations or systemic applications).

Types of participants

The studies selected evaluated individuals with a clinical diagnosis of acute or chronic low back pain, with or without radicular pain, with the presence of pain and functional alterations. All participants were at least 18 years of age.

Types of intervention

Studies in which individulas were treated with one or more IIOLPM procedures were included. In clinical trials, individuals in the comparison groups were treated with placebo interventions, drug treatment, physiotherapy, exercise programs, and epidural steroid infiltrations; other co-interventions were allowed, provided they were uniform in all groups.

We excluded studies where treatment with IIOLPM was applied combined with infiltrations in another anatomical location (intradiscal, intraforaminal) or with other forms of ozone application (rectal insufflation, autohemotherapy), as well as studies where cointerventions were not uniformally performed in all study groups. Only studies that described in detail the intervention performed, the forms of evaluation and their results were chosen.

Measurement of results

We included studies that expressed their results through the evaluation of self-reported pain. Their results had to be evaluated in terms of pain reduction according to the Visual Analogue Scale (VAS) or in terms of the individual’s improvement and / or resolution of symptoms. The results were categorized according to the follow-up time, in the short-term (<6 weeks), medium-term (10-12 weeks) and long-term (>24 weeks).

Data sources and searches

We performed an exhaustive search using the electronic databases PUBMED, SCOPUS, SCIELO, DIALNET and other electronic sources including Google Scholar. This search ranged from January 2000 to December 2019. We used the following keywords: ozone “or” ozone therapy “or” ozone injections “and” low back pain “or” lumbar disc herniation “and various combinations between them.

Evaluation of the risk of bias and methodological quality of the studies included

Based on the Cochrane Handbook for Systematic Reviews recommendations, version 5.1 [32] two investigators independently assessed the methodological quality and risk of bias of the clinical trials included. The following domains were evaluated: generation of random sequence (selection bias), allocation concealment (selection bias), blinding of participants and staff (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (report bias) and other biases. The risk of bias for each domain was classified as low, high, or uncertain. A trial was considered to have low bias risk only when all domains were rated as low. If 1 or 2 domains were classified as high or uncertain risk of bias, the trial was considered to have a moderate bias risk; if 3 or more domains were classified as high or uncertain risk of bias, then it was considered a trial with high bias risk. The evaluation summary of the risk of bias is shown in Figure 1.

The methodological quality evaluation of the observational studies was done using the Coleman scale [33], which consists of 10 scoring domains separated in 2 parts. Part A consists of 7 domains (sample size, follow-up time, number of procedures performed, study design, diagnostic certainty, description of the conservative procedure given and description of post-intervention rehabilitation). Part B consists of 3 domains (criteria to evaluate the results, procedures to evaluate the results and description of the subject selection process). The minimum score is 0 and the maximum score is 100. For our study, we adapted this scale to non-surgical procedures as described by Abdul-Wahab, et al. [34]. The methodological quality was classified according to the score obtained [34]: <70 points = poor, >70 but <80 points = fair, >80 but <90 points = good, >90 points = excellent. The summary of the methodological quality evaluation of observational studies is shown in Table 1.

Data extraction and quality assessment

Two reviewers independently examined titles, abstracts and full texts and determined the eligibility of each study. For the eligible studies, data were extracted independently: study design, risk of bias, clinical configuration, characteristics of the participants, characteristics of the interventions, results, duration of follow-up and adverse reactions.

Data synthesis and analysis

It was not possible to perform the quantitative analysis of the clinical trials, due to the high variability in their expression of results, insufficient data to perform the analyses and high risk of bias of the studies. To homogenize and analyze the results, the percentage of improvement was calculated by comparing the level of pain reported during the initial evaluation versus the final evaluation (initial EVA mean - final EVA mean) / initial EVA mean) in the studies that reported their results this way. On the other hand, in studies where the results were reported as a percentage of individuals who presented remission of symptoms or improvement, this value was taken as a percentage of efficacy, according to the criteria of improvement established in each study.

Role of the Funding Source

This study was not funded by any institution.

Results

A total of 254 citations were identified; of those, 146 were duplicates. The titles and abstracts of the remaining 108 studies were examined, then we excluded 59 studies that were basic or animal model studies, editorials, comments and others. Fiftynine studies were studied in full text, of which 50 were excluded for the following reasons: review studies (n=10), case reports (n=7), studies in which different infiltrations were applied to the paravertebral intramuscular modality lumbar or concomitantly applied to other forms of ozone application (n=33). In the end, nine studies, four observational studies [35-38] and five clinical trials [39-43] were eligible for inclusion in this systematic review. The included studies resulted in a high risk of bias and low methodological quality. The flow chart of the systematized search is shown in Figure 2.

The observational studies comprised 603 individuals diagnosed with low back pain with or without radicular pain who were treated with IIOLPM and 84 controls. The clinical trial comprised 308 individuals diagnosed with low back pain with or without radicular pain who were treated with IIOLPM and 234 controls who received other treatments such as drug treatment, physiotherapy and / or physical exercise programs, as well as placebo infiltrations and epidural infiltrations with corticosteroids. The characteristics of studies ar showed in Table 2.

Efficacy of IIOLPM according to type of intervention

In four studies [36-39], all groups were treated with interventions that included IIOLPM, and a significant percentage of pain improvement was found when comparing basal evaluations vs. short and medium term evaluations (Figure 3a). Three studies [35,40,42] compared IIOLPM vs. non-invasive treatments such as kinesiotherapy, physiotherapy and pharmacological treatment, and the percentage of pain improvement was in favor of the groups treated with IIOLPM at short, medium and long term (Figure 3b). Two studies compared IIOLPM vs. invasive treatments such as placebo infiltrations [41] and epidural infiltrations with corticosteroids [43], and the percentage of pain improvement was in favor of the groups treated with IIOLPM at short, medium and long term (Figure 3c).

Efficacy of IIOLPM according to follow-up time

Eight studies [35-38,40-43] followed up in the short term and in all of them the percentage of pain improvement was significant when comparing baseline evaluations vs. short term evaluations in favor of the groups treated with IIOLPM (Figure 4a). Four studies [37,39-41] followed up in the medium term and in all of them the percentage of pain improvement was significant when comparing baseline evaluations vs. medium term evaluations in favor of the groups treated with IIOLPM (Figure 4b). Three studies [40,41,43] followed up in the long term and in all of them the percentage of pain improvement was in favor of the groups treated with IIOLPM (Figure 4c).

Efficacy of IIOLPM according to time of evolution

Two studies evaluated the efficacy of IIOLPM in patients with acute or subacute low back pain [40,41], finding that the percentage of pain improvement was in favor of the groups treated with IIOLPM in the short, medium and long term (Figure 5a). Five studies [35-37,42,43] evaluated the efficacy of IIOLPM in patients with chronic low back pain in the short-term and the percentage of pain improvement was significant when comparing baseline evaluations vs. short term evaluations in favor of the groups treated with IIOLPM (Figure 5b). Three studies [37,39,43] evaluated the efficacy of IIOLPM in patients with chronic low back pain in the medium and long term, finding that the percentage of pain improvement was significant when comparing baseline evaluations vs. medium or long term evaluations in favor of the groups treated with IIOLPM (Figure 5c).

Frecuency and type of application

With regards of the application characteristics of paravertebral ozone, we found a mode of 12 total applications per patient treated, with a range of 1 to 15 applications. These were applied with a frequency of 1 to 3 times per week with a mode of 2. The volume of gas used per application had a mode of 10ml (range 5-20 ml), at a concentration between 15 and 40 mcg/ml, with a mode of 20 mcg/ml. On the other hand, the application technique used in all studies was intramuscular injections in the lumbar paravertebral muscles, 2 cm from the spinous process of the affected level, including or not the immediate upper and lower levels; however, the depth reached by the needle was not specified in all studies.

Adverse reactions

Regarding the adverse reactions and side effects reported in individuals who received IIOLPM, four studies [36,38,41,43] reported absence of adverse reactions or side effects. Four studies [35,37,39,40,42] reported local adverse reactions such as ecchymosis, burning pain, feeling of heaviness, itching and papules; while three studies [35,40,42] reported cardiovascular adverse reactions such as tachycardia, transient headache, hypotension and syncope.

Discussion

The objective of this study was to analyze the efficacy of ozone infiltrations in paravertebral muscles in patients with low back pain with or without radicular pain.

Two studies [36,37] only included groups treated with IIOLPM without a control group, and evaluated the efficacy by comparing baseline evaluations vs subsequent evaluations, finding that in the short and medium term the improvement in pain was significant. In both studies, in addition to individuals with low back pain secondary to disc disease, they also included individuals with lumbar canal stenosis, spondylolisthesis or a history of spinal surgery with or without radicular pain, reporting good therapeutic response to treatment with IIOLPM; these results are interesting since no other study had treated patients with these diagnoses with the application of IIOLPM, which could open a therapeutic possibility of these pathologies.

Some studies compared IIOLPM vs non-invasive treatment. Two of them compared IIOLPM vs kinesiotherapy programs [35,38] finding a greater benefit in the groups treated with IIOLPM. Other studies compared IIOLPM versus pharmacological treatment [40] or combination of pharmacological treatment + physiotherapy [42] finding a greater benefit in the groups treated with IIOLPM. Non-pharmacological measures [4,6] and nonsteroidal anti-inflammatory drugs [5,9] represent the first line of treatment in case of low back pain. According to these results, the IIOLPM could be an additional treatment in case of not achieving the expected improvement with the non-invasive treatment or they could be used simultaneously.

On the other hand, two study has compared the IIOLPM versus other invasive procedures. Paoloni, et al. [41] compared the efficacy of IIOLPM against the use of placebo and reported a significantly higher percentage of individuals with resolution of acute low back pain when treated with IIOLPM compared to the placebo group. It is possible that the benefits of applying infiltrations to paravertebral muscles in individuals with low back pain could be based on the mechanical effect of needle stimulation in muscles to eliminate trigger points, as it has been reported that dry puncture is effective in pain reduction of individuals with chronic low back pain [44]. However, the study by Paoloni, et al. [41] reported greater efficacy of IIOLPMs than the “mechanical effect of the needle” of placebo injections; this could be due to the regulatory effect of oxidative stress and the restoration of local redox balance, as reported by León-Fernández, et al. [45]. Zambello, et al. [43] compared the IIOMPL versus epidural steroid infiltration in patiens with chronic low back pain with radicular pain, reporting a significantly higher percentage of individuals with pain resolution in a group treated with IIOLPM when compared to a group treated with epidural infiltration. Epidural infiltration probably represents the most commonly used interventional procedure for the treatment of low back pain that does not respond to non-invasive treatment [12,13] and IIOLPM appear to be an effective alternative.

On the other hand, the therapeutic effect of IIOLPM in patients with low back pain, apparently begins in the short term and can be maintained for up to 6 months, as reported in studies with this follow-up period [40,41,43]. Furthermore, this favorable effect can also be observed in patients with acute and chronic low back pain. Although in the majority of cases of acute low back pain will be self-limited and will be resolved within the following 6 weeks regardless of the treatment [46], the 2 studies evaluating the efficacy of IIOLPM in patients with acute low back pain reported benefits in favor of groups treated with IIOLPM.

On the other hand, the doses used were analyzed; based on the reported results, it seems that the dosage of IIOLPM to achieve therapeutic effects for treating of low back pain is 10 ml of ozone at a concentration of approximately 20 mcg/ml per application point, 2 times per week, for a total of 12 applications. However, Araimo-Morcelli, et al. [39] indicate that applications of low volumes of gas (5 ml) under ultrasound guidance, have the same effectiveness than applications of larger volumes (10 ml) with anatomical technique.

Finally, we also analyzed side reactions and / or adverse effects of the application technique. We observed that the most frequent side effects and adverse reactions were local reactions such as ecchymosis, burning pain, feeling of heaviness, itching and papules that resolved favorably, and no one had serious complications. According to the study by Araimo-Morcelli, et al. [39], adverse reactions such as local discomfort can be reduced by applying a smaller volume of gas under ultrasound guidance, with the same effectiveness as the application of larger volumes.

Only one case of paravertebral abscess has been reported in the medical literature as a complication of IIOLPM application [47]. This complication is the only severe complication observed in individuals treated with IIOLPM. In other type of applications such as intraforaminal [48], side effects such as fibrosis and soft tissue adhesions to bone structures or nerve roots to the dural sac have been reported. Regarding intradiscal application, cases of discitis [49], radicular lesions [50], septicemia [51] and even cerebral vascular event [52] have been observed; nevertheless, in a meta-analysis [21] the probability of complications secondary to intradiscal ozone application procedure was only 0.064% (95% CI, 0.000% - 0.136%), which represents a very low percentage for this modality. Based on the above mentioned, we could consider that IIOMPL applications have lower risk of complications compared with other forms of application such as intraforaminal or intradiscal. Likewise, due to the less complexity in the technique application and the less infrastructure needed, IIOMPL could be very useful and its use could facilitate the treatment of individuals with low back pain.

Although the IIOMPL is an interventional procedure for low back pain that has not been recommended in clinical practice guidelines, given its low technical complexity and low risk of adverse events, it could represent an invasive treatment option for the control of acute low back pain and chronic, when non-invasive or other interventional treatments with greater clinical evidence such as epidural corticosteroid infiltration or facet infiltration have not had the expected results.

Previous review studies have analyzed the efficacy of ozone infiltrations in reducing back pain [21,22,53,54]; nevertheless, only Magalhaes, et al. [21] included in its review 2 studies where ozone infiltrations in lumbar paravertebral muscles were used, proposing a level of evidence1B for this intervention.

In our review we found a beneficial effect of IIOLPM in reducing acute and chronic low back pain n the short, medium and long term; however, the poor methodological quality and the high risk of bias of the nine studies included, do not allow us to establish a level of evidence and recommendation for IIOLPM.

Limitations

We acknowledge that our study has some limitations. It is important to note that all of the studies included had a high risk of bias and some had a poor methodological design. Similarly, the lack of a control group in some studies decreased the quality of the evidence. Finally, the number of studies included in this review is very small. Nonetheless, there is little scientific evidence on the subject, so we consider this work to be usefull for future clinical research studies and treatment options for individuals with low back pain.

Conclusions

Although the reported results indicate that ozone infiltrations in the lumbar paravertebral muscles were effective in reducing pain in patients with acute and chronic low-back pain in the short, medium and long term, the low methodological quality and the high risk of bias of the studies included, do not allow establishing a solid level of evidence and it is not possible to recommend it as a routine intervention in individuals with low back pain. However, the favorable results and low risk of complications reported, as well as the low technical complexity of the procedure, suggest that ozone infiltrations in lumbar paravertebral muscles could be a therapeutic tool useful in the treatment of acute and chronic low back pain when other interventions with more evidence have failed; clinical trials of good methodological quality, low risk of bias, greater number of patients and longer follow-up periods are necessary to clarify the efficacy and safety of this intervention.

Author Contributions and Acknowledgments

Concept/idea/research design, writing, data collection, data analysis, project management and consultation (including review of manuscript before submitting): All authors participated equally in the manuscript.

Funding

The present investigation did not receive any specific grant from public, commercial, or non-profit agencies.

Disclosures

The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.

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