News ed Eventi

1. PubMed from 1966 www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed

2. EMBASE from 1980 www.embase.com/

3. Cochrane Library www.thecochranelibrary.com/view/0/index.html

4. DARE and HTA
Search period included from 1966 through Septem-

ber 2011.

1.4.1 Search Strategy

The search terminology included the terms ozone- therapy, ozone, ozone therapy, chronic low back pain, back pain, pain, failed back surgery syndrome and ozonucleolysis.

At least 3 of the review authors independently, in a standardized manner, performed each search. Accu- racy was confirmed by a statistician. All searches were combined to obtain a unified search strategy. Any dis- agreements between reviewers were resolved by a third author and consensus.

1.4.2 Assessment of Methodological Quality

The methodological quality assessment was per- formed by 3 reviewers and any discrepancies were eval- uated by a fourth reviewer and consensus was reached.

The quality of each individual article included in this analysis was assessed by modified Cochrane review criteria with weighted scores (10) for randomized tri- als and the Agency for Healthcare Research and Quality (AHRQ) quality criteria for assessment of observational studies (11). Only the observational studies scoring at least 50 on weighted scoring criteria were included for analysis. Methodological quality assessment criteria are described in Tables 1 and 2.

1.5 Data Extraction and Management

Three review authors independently extracted the data from the included studies. Disagreements were re-

solved by discussion among the 3 review authors; if no agreement could be reached, it was planned a fourth author would decide.

1.6 Measurement of Treatment Effect and Data Synthesis (Meta-analysis)

The authors used a standardized data extraction form for independent inclusion of the study popula- tion, intervention, study design, and outcome measures for randomized controlled trials. The meta-analysis was performed using the Review Manager 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copen- hagen, Denmark) with the random-effect model. Di- chotomous data were compared using odds ratio (OR). Respective 95% confidence intervals (CI) were calculat- ed for each estimate and presented in forest plots. The pooled OR, symbolized by a solid diamond at the bot- tom of the forest plot (the width of which represents the 95% CI), is the best estimate of the true (pooled) outcome. The effect of the treatment was expressed as a ratio of the ozone therapy arm over the control arm.

1.7 Analysis of Evidence

Analysis was conducted using 5 levels of evidence, ranging from Level I to III with 3 subcategories in level II, as illustrated in Table 1(12).

1.8 Recommendations

Grading recommendations were based on the cri- teria stated by Guyatt et al (13) as illustrated in Table 2.

1.9 Outcomes of the Studies

A study was judged positive if the ozone injections were clinically relevant and effective. Regarding random- ized studies, this indicates that the difference in the effect for the primary outcome measure was statistically signifi- cant on the conventional 5% level. In a negative study, no difference between the studied group and the controls or no improvement from baseline was reported (9).

Table 1. Levels of evidence based on the Quality data available in the literature (USPSTF).

Adapted and modified from the U.S. Preventive Services Task Force (USPSTF)(12).

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Table 2. Grading of recommendation

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Adapted from Guyatt et al. grading strength of recommendations and quality of evidence in clinical guidelines. Report from an American College of Chest Physicians task force (13).

2.0 Results

Our search strategy yielded multiple studies evalu- ating the effectiveness of ozone injected into the disc and/or periforaminal or at the paravertebral muscles. From the initial search (117 articles) only 35 were re- viewed: 30 studies, including 7 randomized trials (14- 20) and 23 observational studies, and 5 reports of com- plications (21-25) (Fig. 1).

2.1 Randomized Trials

2.1.1 Methodological Quality Assessment

From the 7 randomized trials, 4 (14-17) met the established inclusion criteria. Three of them were ex- cluded from the meta-analysis: one utilized colagenase (19) associated with ozone and steroid; Gautam et al (20) utilized intradiscal radiofrequency with ozone, and the other due to methodological issues that would in- validate the meta-analysis (18). The results of the meth- odological quality assessment of randomized studies

are illustrated in Table 3. The quality assessment criteria ranged from 56 to 84 points for evidence synthesis.

2.1.2 Descriptive results of randomized studies

In the randomized series of 306 patients, Bonetti et al (14) reported that 57.5% of 80 patients in the disc disease group treated with steroid deemed the clinical outcome to be excellent, as did 62.8% of 70 patients in the group with no disc disease after steroid infiltration (Table 4). Whereas in the ozone therapy group, 74.4% of 86 patients with disc disease reported complete re- mission of pain, as did 75.0% of 70 patients with no disc disease. In this study, differences in favor of O2-O3 treatment were statistically significant in patients with disc disease but not in those without disc disease. In an- other randomized study, Gallucci et al (16) observed a satisfactory success rate with ozone-therapy combined with intraforaminal and intradiscal steroid and anes- thetic injection compared to steroid alone.

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Zambello et al (15) randomized 351 patients with low back pain for treatment with either ozone or ste- roid (epidural) and planned a crossover during the fol- low-up to the other group in case of failure to respond to treatment after 4 weeks of therapy. The long-term outcome remained excellent or good in 47.3% of 171 patients treated by epidural steroid injections and in 77.1% of 180 patients treated with O2-O3. Eleven pa- tients in the ozone group were subjected to crossover to epidural steroid injections whereas 38 patients in the epidural group were submitted to crossover to the

ozone group. Only 36.4% of patients in the crossover group to epidural injection presented excellent/good remission of pain while 70.8% of patients in the epi- dural group who were submitted to crossover to ozone therapy reported an excellent/good outcome.

Recently, Paoloni et al (17) conducted a multicenter, randomized, double-blind, “simulated therapy”-con- trolled clinical trial. Thirty-six patients received intra- muscular-paravertebral ozone injections whereas 24 received simulated lumbar intramuscular-paravertebral injections. The simulated injection was administered us-

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Table 3. Randomized trials on the efficacy of ozone therapy for low-back pain.Criteria

Study population

Scores for methods criteria Author/Country/Year

Zambello (16)/ Italy/2006

Criterion weight

Paoloni (18)/ Italy/2009

Bonetti (15)/ Italy/2005

Gallucci (17)/ Italy/2007

A2B_C-D3E-F

Interventions 9

G 10 H5I5J-

Effect K-L 10

M-N5

Data-presentation and analysis O-P5

Total Score 56 Methodological criteria and scoring adapted from Koes et al (10). Efficacy of epidural steroid for low-back pain and sciatica: A systematic review

ing a false needle that pricked the skin without pierc- ing it, applied at the lumbar paraspinal level, followed by hand-applied pressure on the same site designed to reproduce the load sensation commonly described af- ter O2-O3 injections. Patients who received ozone had significant lower pain scores (mean visual analog scale

[VAS] was 0.66 in the study group and 4.00 in the con- trol group) compared to patients who received simu- lated therapy. Also, a greater percentage of patients became pain-free (61% versus 33%, P < 0.01) in the ozone group. Active ozone therapy was followed by a statistically significant shorter time on nonsteroidal an-

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Table 4. Results of randomized studies of ozone therapy for low-back pain

Ozone Therapy for Low Back Pain

G1 = group 1; G2 = group 2; G3 = group 3; G4 = group 4; WK = week; RA = randomized; P = prospective; O = observational; DB = double blind- ed; B = blinded (patients or evaluator); U = unblended; R = retrospective; CT = tomography; VAS = Visual Analog Scale; MacNab method (excel- lent and good outcome); MRI/MR (magnetic resonance imaging).

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ti-inflammatory drugs, as well as a significant improve- ment on the disability scale in the patient study group compared to the controls.

The outcome measures of the randomized studies were VAS (17,20), Backill scores (17) and drug intake( 17), MacNab’s criteria (15,20), and ODI (16,20).

2.2 Observational Studies

2.2.1 Methodological Quality Assessment

A total of 23 observational studies were consid- ered for inclusion (Fig. 1). Only 8 of these met the methodological quality assessment criteria for inclu- sion (Table 5) (26-33). The results of the methodologi- cal quality assessment showed scores from 50 to 72. Some observational studies met the inclusion criteria, but had an insufficient score in the methodological quality assessment, and thus were only listed in the references (34-46). Furthermore, some studies were excluded for other reasons: one compared ozone therapy with a not well-established treatment (Ala- nerv) for low back pain (47); and Baabor et al (48) used another intervention associated with intradiscal ozone.

2.2.1 Descriptive results of observational studies

Among the observational studies, we observed heterogeneous groups of patients, different follow-up periods, and some discrepancy in the computed tomog- raphy (CT) or magnetic resonance imaging (MRI) evalu- ations of morphological criteria (Table 6). Muto et al published 3 studies between 1998 and 2008 (27,28,29) using intradiscal injection of an oxygen-ozone mixture under CT guidance to treat approximately 3,700 pa- tients and reported an 80% success rate at short-term follow-up (6 months) and a 75% success rate at long- term follow-up (18 months), with no major or minor side effects.

Oder et al (26) studied 621 patients to determine associations among the morphology of the disc disease, patient-specific data, and treatment outcomes. Six hun- dred twenty-one consecutive patients were subjected to CT-guided ozonucleolysis in combination with peri- radicular infiltration by steroids under local anesthe- sia. Based on the MRI findings of the lumbar spine, the patients were retrospectively divided into 5 diagnostic groups: group I consisted of 205 patients (bulging disc); group II had 185 patients (herniated disc); group III had 66 patients (postoperative patients); group IV had 51 patients (primarily intervertebral osteochondrosis); and

group V had 114 patients and included other primary nondiscal changes (intervertebral arthrosis, spinal canal stenosis and pseudoanterolisthesis). The patients re- ceived steroid and an oxygen-ozone mixture into the disc and periganglionic infiltrations by CT guidance. Each patient was monitored for a period of 6 months and documented with the Oswestry Disability Index (ODI) and VAS. Patients younger than 50 years had sig- nificantly better values on the VAS and in ODI scores, 6 months after treatment.

Andreula et al (30) reported a 78.3% success rate in patients treated with ozone therapy and perigan- glionic steroid injection compared with a 70.3% rate in those treated with ozone therapy alone; complica- tions occurred in 2 of 235 patients and consisted of episodes of impaired sensitivity in the lower limb on the treated side, which resolved spontaneously with- in 2 hours. In a series of 45 patients, Buric et al (31) studied the differences in outcome between intradis- cal ozone chemonucleolysis and microdiscectomy in patients with noncontained lumbar disc herniations; they documented that 27 patients (90%) in the che- monucleolysis group showed a statistically significant improvement in pain and function; the same was true in 14 (93.3%) patients in the microdiscectomy group. However, 2 patients dropped out of the ozone chemo- nucleolysis group because of aggravating symptoms and subsequently underwent surgery.

Das et al (33), in an Indian population cohort study, evaluated 53 consecutive patients with lumbar disc herniation. All presented with clinical signs of lumbar nerve root compression supported by CT and MRI findings. They were treated with a single session of intradiscal ozone therapy. Therapeutic outcome was assessed after 2 years. Pain intensity was signifi- cantly reduced following treatment (VAS baseline was 7.58; after 2 years, 2.64). Similar ODI results were seen (P < 0.05). No major complication was observed in this case series.

Xu et al (32) included 187 patients with sciatica and low back pain with positive Lasègue sign and di- agnostic verification by CT and MRI exhibited disc pro- trusion with nerve root or thecal sac compression. They compared the effectiveness rates after one week (103 cases), 2 weeks (61 cases), and 4 weeks (23 cases) treat- ment sessions of intradiscal ozone therapy. They were evaluated by Macnab criteria at 48 months. The effec- tive rate was 82.02% in all groups. However, there were no significant differences in the total effective rate in the 3 groups (P = 0.280).

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Table 5 . Methodological assessment of observational studies of ozone therapy

Weighted Core Points

Author /country/year

Criteria

Clearly focused and appropriate question

2. Study Population

Description of study population

Sample size justification

3. Comparability of subjects

Specific inclusion/exclusion criteria for all groups

Criteria applied equally to all groups

Comparability of groups at baseline with regard to disease status and prognostic factors

Study groups comparable to non-participants with regard to confounding factors

Use of concurrent controls

Comparability of follow up among groups at each assessment

4. Exposure or Intervention

Clear definition of exposure

Measurement method standard valid and reliable

Exposure measure equally in all study groups

Oder Muto Muto

Andrula Muto Buric Xu Das Italy Italy Austria China India 2003 1998 2005 2009 2009

2 2 2 2 2 2 2 2 2 2 5 5 5 5 5 5 5 5 5 5 0 0 0 0 0 14 14 14 11 14

Italy Italy 2008 2008 2004

Austria

5. Outcome measures 20 10 15 10 15 10 15 12 15

Primary/secondary outcome clearly defined

Outcomes assessed blind to exposure or intervenient

Method of outcome assessment standard, valid and reliable

Length of follow-up adequate for question

6. Statistical Analysis

Statistical tests appropriate

Multiple comparisons taken into consideration

Modeling and multivariate techniques appropriate

Power calculation provided

Assessment of confounding

Dose-response assessment appropriate

7. Results

Measure of effect for outcomes and appropriate measure of precision

Adequacy of follow-up for each study group

8. Discussion

Conclusions supported by results with possible biases and limitations taken into consideration

9. Funding or Sponsorship

Type and sources of support for study

505005525

500050000

555550555

55

19 17

5 5

3 3

2 2

2 2

5 5

2 0

8 8

5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 8

5 5 5 0 0 8 0 0 5 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 5 3 8

5 5 7 10 5 5 0 3 0 2 0 0 0 0 2 0 8 8

555500555

333353333

550005535

100 72 52 50 52 50 68 59 70

TOTAL SCORE
West et al. Rating system to measure the strength of evidence, evidence report, technology assessment No. 47 AHQR Publication No. 02-016 (11).

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Table 6 . Results of observational studies of ozone therapy for low-back pain

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Table 6 (cont.) . Results of observational studies of ozone therapy for low-back pain

Ozone Therapy for Low Back Pain

G1 = group 1; G2 = group 2; G3 = group 3; G4 = group 4; RA = randomized; P = prospective; O = observational; DB = double blinded; B = blinded (patients or evaluator); R = retrospective; FBSS = failed back surgery syndrome; CT = tomography; VAS = Visual Analog Scale; ODI = Oswestry Disability Index; McGill = McGill questionnaire of pain; MacNab method (excellent and good outcome); RMDQ = Roland-Morris Disability Ques- tionnaire; OPRS = Overall Patient Rating Scale; MRI/MR (magnetic resonance imaging); EMG (electroneuromyography).

The outcome parameters utilized in the obser- vational studies were MacNab criteria (29,32), VAS ( 26,31,33), ODI (26,29), Roland-Morris (31), and Overall Patient Rating Scale (31). Three authors utilized CT/MRI in their follow-ups (27,28,31) (Table 6).

2.3 Effectiveness

Overall, the observational studies revealed positive results for short- and long-term relief of pain. From the randomized studies, intervention was found superior to the control, with OR 2.66 (95% CI, 1.94 to 3.63), and P < 0.00001 as shown in Fig. 2.

These studies evaluated ozone applied at the para- vertebral muscle and juxtaforaminal at the herniated disc level. Three of them compared ozone injections utilizing an active control group (steroid injections) (14,15,16). Paoloni et al (17) utilized a sham control group with a simulated injection that was administered using a false needle that pricked the skin without pierc- ing it, applied at the lumbar paraspinal level, on the same site designed to reproduce the load sensation commonly described after O2-O3 injections.

2.4 Level of Evidence

The indicated level of evidence is II-3 for ozone therapy applied intradiscally and II-1 for ozone therapy applied paravertebrally on long-term relief in low back pain secondary to disc herniation (12).

2.5 Recommendations

Based on Guyatt et al (13), grading the strength of recommendations and quality of evidence in clinical guidelines, the recomendation is 1C for ozone therapy applied intradiscally and 1B for ozone applied at the paravertebral muscles or periforaminally.

2.6 Complications

Complications secondary to ozone therapy are rarely documented in the literature. In this review, re- garding ozone therapy for low back pain, we encoun- tered predominantly case reports of 5 different types of complications. Giudice et al (22) reported bilateral vitreo-retinal hemorrhages following ozone therapy for lumbar disc herniation. Furthermore, one case of thunderclap headache after oxygen-ozone therapy

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related to pneumoencephalus as a consequence of in- advertent intrathecal puncture was recently published (24). Ginanneschi et al (23) reported a case of a patient who experienced paresthesias along the anterolateral compartment of the left leg and hypoesthesia over the dorsum of the left foot, suggesting spinal nerve injury occurring a few minutes after percutaneous intradiscal infiltration of ozone for L4-L5 disc herniation. In 2004, Corea et al (21) published a report of vertebrobasilar stroke during ozone therapy. In 2 of 235 patients, An- dreula et al (30) reported episodes of impaired sensitiv- ity in the lower limb on the treated side, which resolved spontaneously within 2 hours. Fabris et al (34) reported a subcutaneous hematoma at the puncture site.

3.0 discussion

The present review has added methodological im- provements compared to previous review articles; the search database was wider and covered all languages, focusing on articles that used ozone alone in at least one group of patients. Final evidence was separated by the route of ozone administration. In addition, the au- thors performed a rigorous selection of RCTs that made possible a meta-analysis. Steppan at al (29) published a review in which data was extracted mainly from obser- vational series; one was an unpublished study and one was a randomized trial on intradiscal ozone injections for the treatment of pain related to herniated discs. Although the authors have made a meticulous com- putation of data and wrote similar conclusions about the effectiveness and safety of this method, it probably would not be considered a meta-analysis if it had been submitted to the present review board.

Regarding the observational studies, 23 were ini- tially selected according to the inclusion criteria, but

only 8 could be included according to the rigorous methodological assessment criteria (11). Most studies lost points in the characterization of the study popula- tion because they did not specify the diagnosis. Prob- ably, in future studies the authors should add diag- nostic criteria and if needed, diagnostic procedures. The excluded studies also lack outcome measures and some of them had poor statistical analysis (which was absent in some of them). Furthermore, excluded studies contained heterogeneous populations of patients with low back pain, including patients with lumbar disc her- niation, degenerative disease, acute pain, chronic pain, and patients with and without a history of operations. In addition, regarding the analysis of results, in some studies it was not clear what primary and secondary outcomes were expected; functional scales were diverse and in most cases not comparable. Most comparative studies used statistical analysis to aid the conclusions, but some of them have unacceptable confusion be- tween normal and non-normal data distribution, re- sulting in the inappropriate choice of statistical tests. Furthermore, these studies often do not describe bias and limitations. Some studies include a large number of patients, a long period of follow-up and a careful surgi- cal technique, but do not have appropriate design or statistical analysis (39). Another study did not compare with a method established in the literature, so it was excluded (46).

Among the selected RCTs, 3 of them compared ozone treatment with an active control group (ste- roid or steroid with local anesthetic) and one study compared ozone injection with a sham procedure. No placebo-control study was found among the articles included in this review. This seems to be a tendency when treatment-resistant pain is the issue. Currently,

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ethics committees seem to favor studies based in an ac- tive controls comparison group. In addition, this makes patient recruitment faster because patients have a bet- ter acceptance when there is no placebo involved. Al- though this is not a consensus, it seems logical that an established treatment is probably better than the pla- cebo effect. So, if any new treatment is to be tested, it could be perfectly compared to an active control group and in this way the placebo effect would also be over- come. On the other hand, patients tend to think that new treatments are more efficacious than the estab- lished ones because of their novelty. This makes us think that the novelty usually carries a strong placebo effect. This controversy still keeps placebo-controlled trials as the gold standard methodology. However, in the near future this methodological recommendation will prob- ably be reviewed because practical issues point to more progressive methodology for active control studies in pain literature.

Some of the studies have evaluated the morphol- ogy of the disc by MRI or CT scan during follow-up. Bu- ric et al (31) evaluated the clinical and morphological results of patients with disc disease and observed that 15 of the 30 patients showed clinical improvement, per- forming post operative MRI imaging. Eight of these pa- tients had a substantial reduction of over 50% in her- niation volume. Two patients had a volume reduction of less than 50%, whereas 5 patients had no substantial variation in herniation volume. Muto et al (27) observed a reduction in the size of the herniated disc in only 8 cases out of the 45 patients who had improved. In 2004, Muto et al (28) documented a reduction in herniated disc size in 63% of cases, confirming persistent satisfac- tory outcome. Thus, these authors stated that the equa- tion large herniation = major symptoms, small hernia- tion = minor symptoms, does not always hold true. It seems quite natural to assume that clinical signs and symptoms of disc herniation are not caused only by me- chanical compression but that biochemical factors play an important role in inflammatory sensitization and immune response in the epidural environment of the nerve roots and ganglia. Based on the same reasoning, it seems logical to presume that mechanical removal of herniated tissue may not always be needed and that reducing the inflammatory process could essentially be sufficient to treat the symptoms. This hypothesis was partially confirmed by the cited study (49,50). On the other hand, patients who were clear candidates for sur- gery had no improvement after ozone therapy. Muto et al (27) observed treatment failure in all 35 patients pre-

viously selected for surgery who presented a herniated or protruded disc with radicular pain associated with neurological deficit. In the work of Buric (50), 2 patients dropped out of the ozone therapy group because of ag- gravating symptoms and were subsequently operated on. In another observational study (30), among patients treated with ozone and whose treatment had failed, outcomes were poor in 25% and poor with recourse to surgery in 4.7%. Among the patients in the steroid group and anesthetic injection group, 50 (16.7%) had poor results and 15 (5%) were referred for surgery.

The majority of the studies reviewed included pa- tients with discogenic disease at one or more levels between L3 and S1(14-16,26,27,29-31). However, other series included heterogeneous groups of patients with other primary nondisc diseases such as canal stenosis, postsurgical fibrosis (failed back surgery syndrome), disc protrusion with vertebral instability, facet arthro- sis, calcified herniation, intervertebral osteochondrosis, and pseudoanterolisthesis. In the first group, positive results were achieved in 75-80% of treated patients. In patients with a nondisc disease, the rate of sustained improvement ranged between 44 to 70% in all groups, independent of the morphological classification of the spinal disease (26,28,29). This suggests that ozone ther- apy may have an important role in low back pain relief, independent of the source of disease.

Ozone is a strong oxidizing agent that quickly re- acts and oxidizes the proteoglycans in the nucleus pulp- osus, which results in a small reduction of disc volume and subsequently contributes pain relief. The suggest- ed premise is that a small volume reduction results in a significant decrease in pressure. In addition, it has been shown to have anti-inflammatory/analgesic and natu- ral antibacterial effects (5,52). Additional discussion of ozone’s mechanisms of action can be found elsewhere (51).

Ozone therapy for lumbar disc herniation is a pro- cedure that is considered generally risk-free or as low as 0.1% (48) and has low or no adverse effects at concen- trations used for therapeutic application (10-40 μg/mL). However, in the present review, 6 reports of side effects related to ozone infusion were found. Similar descrip- tions of transitory paresthesia suggested transient root dysfunction, although the mechanisms underlining the reported sensations are still not clear. Assuming the presence of microfractures of the annulus fibrosus, one possibility is that an abrupt, transient pressure spike in the region of the spinal canal and cerebrospinal fluid (CSF) pressure after disc infiltration could be related to

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the transient paraesthetic symptoms. A similar mecha- nism was postulated as the cause of acute bilateral intraocular hemorrhages after injection of the O2-O3 mixture (22). Concerning the pathophysiology of the lesion, it could be hypothesized that an abrupt and transient increase of CSF pressure causes focal damage by means of mechanical transmission of pressure in the CSF, manifesting in the form of direct root trauma. The occurrence of retinal hemorrhages immediately after rapid injection of air into the subarachnoid space dur- ing myelography or after epidural injection of cortico- steroids has also been previously described (52,53).

Infection secondary to oxygen-ozone injection therapy is extremely rare. Recently, Gazzeri et al (25) reported a case of fatal septicemia secondary to Esch- erichia coli infection after ozone therapy for lumbar disc herniation, in which a pyogenic lumbar muscle in- volvement and septic pulmonary embolism were pres- ent. The most likely pathophysiological mechanism in these cases was probably iatrogenic; that is, the direct inoculation of the bacteria by injections due to an inad- equate asepsis procedure as has occurred in other per- cutaneous spinal procedures (25,30).

4.0 conclusion

This systematic review and meta-analysis of ozone therapy for low back pain secondary to herniated disc indicated the level of evidence is II-3 for ozone thera- py applied intradiscally and II-1 for ozone therapy ap- plied at the paravertebral muscle and periforaminally for long-term pain relief based on USPSTF criteria (12). The aviable evidence yielded a 1C strength of recom- mendation (13) for ozone therapy applied into the disc and 1B for ozone applied at the paravertebral muscles or periforaminally. The evidence was derived from ran- domized control trials within this meta-analysis and ob- servational studies. In addition, the low costs of ozone therapy may account for its wider use in the percutane- ous treatment of herniated lumbar discs (54) and other causes of back pain. Injections can be repeated if neces- sary and complications or side effects are rare. There- fore, this method may be considered an option to treat lumbar disc herniation-related low back pain that has failed to respond to conservative treatment, represent- ing an alternative to surgery. However, future studies are necessary to demonstrate whether ozone therapy effects persist over time.

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