Does paravertebral ozone injection have efficacy as an additional treatment for acute lumbar disc herniation? A randomized, double-blind, placebo-controlled study

1.Introduction

Acute low back pain (LBP) is an important cause of disability and may frequently occur at any stage of life, disrupting activities of daily living [1]. It is reported that lumbar disc disruption is present in approximately 73% of acute LBP cases, and approximately half of these are associated with lumbar disc herniation (LDH) [2, 3, 4]. In acute LDH, conservative (medication, physical therapy [PT], and exercises) and minimally invasive (epidural steroid injection [ESI]), nonsurgical treatments yield satisfactory results [2, 5, 6]. However, certain patients may not respond to these treatments or experience relapse [6]. Sometimes, the use of these treatments may not be possible because of side effects or contraindications [2, 5]. Short-term use of non-steroidal anti-inflammatory drugs and analgesics is recommended because of the risk of side effects [7]. Although PT modalities (ultrasound, laser, traction, TENS, and thermotherapy) are commonly used in clinical practice, there is no consensus in the literature on their effectiveness [8]. Epidural steroid injections (ESI) are known to be effective in short-term pain relief in acute LDH [9]. However, the use of ESI may be limited because of potential side effects and contraindications associated with the drugs used (corticosteroid, local anesthetic, and contrast agent) or injection [10].

Although the success rate of surgical treatment is high, it is only recommended to patients who have progressive neurological deficits or are unresponsive to conservative treatments due to probability of relapse and complications. Therefore, it has been suggested that minimally invasive, well-tolerated, and low-cost ozone therapy (OT) can be used as a complementary treatment for patients with LDH who do not respond to conservative treatments before resorting to surgery or when surgery is not possible [2, 11, 12, 13, 14]. OT can be administered through intradiscal, epidural/intraforaminal, and paravertebral intramuscular injections. Intradiscal or epidural ozone injections can be performed under sedation and with the help of radiological imaging (fluoroscopy and computed tomography) [15]. On the contrary, paravertebral ozone injections (POI) are a relatively easy and less invasive technique that can be performed in outpatient clinic conditions without the need for sedation and radiological imaging and may therefore be preferred [2, 16, 17]. However, to the best of our knowledge, no study comparing these methods in terms of efficacy was found in the existing literature.

Ozone is an unstable form of oxygen, and free radicals formed upon contact with body tissues cause light and transient oxidative stress, thereby stimulating the upregulation of the antioxidant system, the modulation of the immune system and the suppression of inflammatory processes. Thus, it is used as a complementary modality in the treatment of many degenerative, inflammatory, vascular, or infectious diseases [12, 18]. By injecting ozone directly into paravertebral muscles intradiscally or indirectly in LDH, it has been reported that it can reduce the disc volume and have anti-inflammatory and analgesic effects [19, 20, 21, 22]. Although ozone injections in many European and Asian countries are used with increasing popularity in LDH, there are few studies on their efficacy, many of which are based on the results of intradiscal and intraforaminal ozone injections [13, 15, 20, 23]. There are no placebo-controlled studies; however, there are a few studies with active control groups among a small number of studies using POI [2, 5, 7, 24]. Therefore, the authors believe that this randomized controlled trial (RCT) conducted to determine the efficacy of POI as an additional treatment in decreasing the pain and disabilities in patients with acute LDH will have significant contributions to the literature.

2.Materials and methods

2.2Participants

This study included patients who were 18 to 60 years old, had LBP (radicular or non-radicular pain) (with a VAS score of 5 and above) complaints for the first time and for 4 weeks and less, and were diagnosed with acute LDH. The diagnosis of LDH was made in the presence of clinical findings (manual muscle testing, positive supine straight leg raise test, dermatomal pain, sensory deficits, and reflex deficits) consistent with protrusion or extrusion image at the L3-L4, L4-L5 or L5-S1 levels reported by the radiologist in lumbar magnetic resonance imaging (MRI).

Figure 1.

Study flowchart.

The study was conducted between December 2019 and May 2020 at the PT and rehabilitation clinic of Private Nisa hospital. The exclusion criteria in terms of OT included pregnancy, lactation, hyperthyroidism, favism (glucose-6 phosphate dehydrogenase enzyme deficiency), sickle cell anemia, hypoglycemia, hypotension, and exogenous antioxidant vitamins use (vitamins A, C, E, and B9). The exclusion criteria in terms of LDH included spondylolisthesis, spinal stenosis, muscle weakness due to radiculopathy, previous history of lumbar surgery, and lumbar paravertebral or intradiscal or epidural injections (ozone, steroid, local anesthetic, prolotherapy, acupuncture, and dry needling) in the last 4 weeks.

3.Results

Of the 65 patients with acute LDH evaluated in the study, 46 met the study criteria and were randomly divided into two groups. Twenty of the 23 patients in the OT group and 18 of the 23 patients in the PC group completed the study. 8 patients (OT: 3 (13%); PC: 5 (21.7%)) discontinued the study before completion (Fig. 1). Table 1 summarizes the clinical features of the patients. There was no significant difference in the baseline (V1) VAS and ODI scores between the two groups (P> 0.05) (Table 1).

Fifteen (65.2%) patients in the OT group and fourteen (60.9%) patients in the PC group received the PT program (P> 0.05). The medication therapies of the patients in both the groups were similar (P> 0.05) (Table 1).

The patients in the OT group had lower VAS scores in V2, V3, and V4 periods compared with those in the PC group. Starting from V3, this difference became significant and reached its peak in V4 (mean difference 2.2) (F= 37.367; ηp2= 0.459; P< 0.0001) (Fig. 2).

Figure 2.

Mean VAS scores at different follow-up in OT group (black bars) and PC group (gray bars). Lower values correspond to clinical improvement.

Figure 3.

Mean ODI scores at different follow-up in OT group (black bars) and PC group (gray bars). Lower values correspond to clinical improvement.

When compared to the baseline (V1) ODI scores, there was a significant improvement in the V2 (mean difference = 10.6; F= 7.889; ηp2= 0.152; P= 0.007), V3 (mean difference = 15.2; F= 25.792; ηp2= 0.370; P< 0.0001), and V4 (mean difference = 23.1; F= 72.453; ηp2= 0.622; P< 0.0001) ODI scores of the patients in the OT group compared with those of the patients in the PC group (P< 0.05) (Fig. 3). In addition, there was a significant improvement in VAS and ODI scores between baseline (V1) and final follow-up (V4) in both groups (P< 0.05) (Figs 2 and 3).

At the end of the follow-up, the VAS scores fell below 5 in 100% of the patients in the OT group and in 38.8% of the patients in the PC group. Furthermore, 3 patients became completely pain-free in the OT group.

Load and fullness sensation and mild pain in the lumbar region lasting several hours during the ozone injections were observed in all the patients, more pronounced in the patients of the OT group. These adverse effects, which were more common during the first sessions, gradually decreased in the subsequent sessions. No other side effects were observed during the follow-up period. Since the follow-up process was short, no patient underwent a control MRI.

4.Discussion

In this study OT was used as an additional treatment in patients with acute LDH who were diagnosed with LDH for the first time and had no absolute surgical indications. There were significant improvements in the pain and disability scores of the patients in the OT group compared with those in the PC group.

Minimally invasive OT methods (intradiscal, epidural, and paravertebral), which have been widely used in treating many diseases in recent years, are used in treating LDH [2, 11, 12, 13]. In treating acute LDH, there are other effective conservative therapies (PT modalities, exercises, and ESI) [2, 5, 7]. However, in cases where these treatments cannot be performed or no response is obtained or surgery is not possible, POI, a minimally invasive OT application, may be required because it has some advantages.

PT modalities (ultrasound, laser, traction, TENS, and thermotherapy) are commonly used in clinical practice in treating acute LDH [32]. Tailored therapeutic exercises and spinal manipulation can be effective options [8, 9]. Most therapists consider these interventions to be effective [32, 33]. Although there are studies that support this [32, 34], there is insufficient evidence in the treatment guidelines to make a recommendation for or against the use of these modalities [8, 9]. Because of this contradiction between the use of PT applications in clinical practice and the recommendations in the guidelines, the effectiveness of PT is still under discussion. Despite these discussions, this study also used PT modalities and therapeutic exercises in terms of their effectiveness in treating LDH, and results that support the complementary role of the additional POI application have been reached.

ESI is recommended in LDH treatment guidelines because of its pain-relieving properties in patients who do not respond to other conservative treatments [8, 9]. Although this intervention is generally shown to be safe, it is known that it has certain risks [10]. These risks are potential side effects arising from the injection itself (headache because of dural perforation, bleeding, infection, and vasovagal reaction) or the pharmacological agents used (allergic reactions, increased blood sugar, mood changes, and insomnia) [10]. The use of ESI may be limited by such side effects and contraindications such as uncontrolled diabetes mellitus [10]. In such cases, POI, which is a more superficial percutaneous injection that does not have any corticosteroid or local anesthetic side effects and is not related to dura, may be preferred. Furthermore, POI may be preferred over ESI because it can be applied relatively easily in outpatient clinic conditions without the requirement for sedation and imaging assistance [2, 16, 17].

In LDH, intradiscal, intraforaminal, and POI exhibit some direct and indirect mechanical and anti-inflammatory effects [2, 11, 12, 13, 14]. It is reported that ozone has an effect on activating proteoglycans, on reducing ischemia and venous stasis, on reducing the release of pro-inflammatory cytokines (interleukin (IL)-1, IL-2, IL-8, IL-12, IL-15, interferon-α and tumor necrosis factor-α), and on increasing the release of immunosuppressor cytokines (transforming growth factor-β 1 and IL-10) [2, 5]. All these effects suggest that ozone can reduce the disc volume and nerve root pressure and have anti-inflammatory and analgesic effects [5]. Thus, ozone may have positive results on the mechanical compression and inflammatory responses of the disc responsible for the pathophysiology of pain in LDH [35, 36]. Furthermore, it has been reported that ozone injection at the paravertebral level can exert its effects even far from the application site because of its local antiphlogistic properties that improve axonal function [2]. In addition, it is possible to achieve analgesia by creating a direct effect on the possible trigger points with POI [2, 12]. Therefore, POI, which lead to a complex set of chemical and neurological reactions that result in a reduction in pain in LBP with both needle and gas injections, were called “chemical acupuncture” by Bocci [37]. The authors believe that the improvement in the pain scores in this study may have resulted from the anti-inflammatory effect of the POI and their effect on the trigger points.

Intradiscal and intraforaminal ozone injections have been used in the treatment of LDH for over 20 years [23, 38]. In a few studies on these procedures in the literature, clinical success of up to 70–80% was reported [23, 38]. In their review, Magalhaes et al. [20] reported the evidence level of intradiscal OT for long-term pain relief as strong recommendation and low quality. In the same review, the evidence level of paravertebral OT was reported as strong recommendation and medium quality. However, data regarding OT are limited because of the absence of a placebo-controlled study in this meta-analysis and the fact that the two paravertebral ozone RCTs [2, 5] were performed with an active control group [20]. To the best of the authors’ knowledge, this study was the first POI study conducted with a PC group. In most studies conducted, POI were administered to patients with chronic LBP. To the best of the authors’ knowledge, this study is the third one conducted in an acute LDH setting [2, 24].

In the literature, authors found three RCTs [2, 5, 24], one prospective non-RCT [7], and three retrospective [11, 14, 17] studies on the treatment of LBP with POI. In these studies, with non-PC groups, POI were compared to analgesic and anti-inflammatory drugs [24], simulated therapy [2], global postural re-education [17] and epidural steroid [5] administration as active control groups, and they all found more significant improvements in the pain and disability scores in favor of OT. In this study, improvements in the pain and disability scores of the patients in the OT group were more significant compared with those of the patients in the PC group. Melchionda et al. [24] reported that the success rate of POI compared with analgesic and anti-inflammatory drugs was 50% vs. 16.6% in the second week and 80% vs. 50% in the 6-month follow-up. Paoloni et al. [2] found that 61% of the patients in the paravertebral ozone group and 33% in the simulated therapy group became pain-free after 6 months of follow-up. Out of 351 patients with chronic LBP, Zambello et al. [5] treated 171 patients with epidural steroid and 180 patients with POI. Total or near-total remission of pain was observed in 88.2% of patients in the OT group in the short term (three weeks) and 77.1% in the long term (six months). These rates were 59% and 47.3%, respectively, in the epidural steroid group.

There is no consensus in the literature on the standard ozone doses and concentrations in POI. Paoloni et al. [2] administered POI at a concentration of 20 μg/ml in a volume of 20 ml 3 times a week for 5 weeks, Biazzo et al. [14] administered POI at a concentration of 27 μg/ml in a volume of 20 ml twice a week for 6 weeks, and Özcan et al. [11] administered POI at a concentration of 15 μg/ml in a volume of 50 ml once a week for 6 weeks. Based on the recommendations of SIOOT [26] and MDOT [25], it is reported that the concentration of ozone is 10–20 μg/ml, the total volume is 5–40 ml, and the total dose is 50–400 μg. It has been reported that the frequency of administration can be up to 20 sessions, starting with two sessions per week and continuing with once a week or every other week. Bocci et al. [12] reported that the ozone concentration should not be below 18 μg/ml or higher than 25 μg/ml. They stated that low doses may be ineffective, while high doses may cause severe pain and risky vasovagal reflex. In this study, taking into account all these procedures and recommendations, the authors determined the ozone concentration to be 20–25 μg/ml, its volume to be 30 ml, and its frequency to be twice a week for 4 weeks in the OT group.

Side effects reported in POI are extremely rare. Infection, a common risk for any invasive procedure, has been reported in POI. There is one case of death in the literature becaus of pyogenic muscle involvement and fulminant septicemia following POI [39], and one case of paravertebral and intraabdominal abscess that developed two months after POI and was treated with antibiotic therapy [40]. These infections may have been caused by the lack of sterility in the injection area during the procedure and that close attention should be paid to sterility. The authors performed the procedures in this study under sterile conditions and did not encounter any infection during the follow-up period. Moreover, it is known that ozone has antimicrobial and disinfectant properties [41]. Except for the possible risk of infection in POI, no significant side effects were reported except for mild pain in the injection area and fullness sensation and transient ecchymosis, which were reported in the literature and observed in our study [2, 11, 12]. This supports the idea that POI can be safely administered at the recommended dose range after the necessary sterility conditions are met.

5.Conclusion

Although there are other effective conservative treatments in acute LDH, it can be said that, as an additional treatment combined with conservative treatment, lumbar POI can lessen pain and disability. It can be concluded that these minimally invasive ozone injections can be used as an effective complementary intervention to treat acute LDH. However, RCTs with a higher number of patients and longer follow-up periods are still needed.

Author contributions

HS: Conceptualization, methodology, writing – review and editing, data curation, formal analysis. NS: Methodology, data curation

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.