Paravertebral intramuscular ozone therapy in lumbar disc hernia: A comprehensive retrospective study

Abstract

BACKGROUND:

Clinical studies assessing the impacts of ozone on the musculoskeletal framework are slowly expanding.

OBJECTIVE:

In this study, we analyzed the impact of paravertebral ozone treatment (OT) injection treatment on distress and disability in patients with lumbar disc hernia (LDH).

METHODS:

The records of 432 patients with L4-5 and L5-S1 LDH were examined retrospectively. 298 patients who met the inclusion criteria and who provided written informed consent were divided into two groups. Each group received 15 sets of physiotherapy at a rate of five sets every week (study group ( $n=$ 139), control group ( $n=$ 159)). Six OT injections were applied solely to the study group, two days per week. A visual pain score (VAS) was set up for distress and the Oswestry Disability Questionnaire (ODI) for disablement was administered when the groups were called to control before treatment, towards the end of the treatment, and three months after the treatment ended.

RESULTS:

The groups had significantly reduced ( $p<$ 0.05) VAS and ODI scores following and three months after the treatment contrasted with their scores before the treatment. The Physiotherapy $+$ OT group had significantly lower ( $p<$ 0.05) VAS and ODI scores than the physiotherapy group following and three months after the treatment.

CONCLUSIONS:

Paravertebral OT injection is quite a safe and helpful treatment technique in LDH patients. Further studies should be conducted to investigate the long-term outcomes of the paravertebral OT application.

Keywords

Lumbar disc herniation pain ozone therapy physiotherapy

1. Introduction

Lumbar disc hernia (LDH) is described by lower back and leg distress resulting from a deteriorated disc compacting the lumbar spinal root. Circumferential tears happen first in strong annulus fibrosis strands and radial tears with the merger of circumferential tears later on due to biochemical and biomechanical alterations. By entering the nucleus into various annular tears, it makes circumferential (annular) bulging. A herniation is divided into three groups: localized disc overflow is named protrusion, while extrusion happens when the annulus is entirely cracked and the core comes into the canal. In the event that the herniated material is broken and delivered in the epidural space, it is termed sequestrated plate or free fragment [1]. The primary complaint of patients with LDH is low back and leg pain. Most patients are aged between 30 and 50, however, LDH cases are experienced in childhood and adolescence as well [2]. Nearly 90% of all disc herniations in the spine are observed in the lumbar region. Only 5% of cases with low back pain are disc herniated and approximately 95% of LDHs are at L4-L5 and L5-S1 levels [3].

LDH can be managed using conservative and surgical methods [4]. With a conservative treatment, complaints may be reduced by giving information about alterations in habits, appropriate exercise plans, weight loss, aims of treatment, and other precautions [5, 6]. Chronic low back pain limits physical activities, functional deficiencies, and results in a decreased quality of life and important labor loss [7, 8, 9, 10]. Engaging in physical activity and exercise programs has positive effects on the complaints of people with LDH [11, 12]. Those with symptomatic disc herniation/radicular low back pain are primarily treated with conservative methods except in cases of acute or progressive neurological deficiencies. Several physical medicine and rehabilitation (PMR) methods and pain-decreasing medications may be adequate, and surgery is usually not necessary while treating comprehensive disc herniation to ease symptoms, preserve function and guarantee social involvement of the individual. Although the efficiency of PMR methods is not widely known, when compared to the surgical methods, conservative techniques may have lower risks and are less expensive for many people who have disc pathology. There is no significant difference in the findings such as distress, physical function, and disablement in patients who had or did not have surgery in sciatica resulting from LDH after one or two years regardless of the agreement on the fact that surgery is suitable for those who do not efficiently respond to conservative methods [13, 14]. Thereby, it is crucial to ascertain the most efficient conservative methods through scientific proof in those with low back pain and especially LDH considering that in such cases in which open surgery is the standard surgical method, there is a high ratio of the probability of complications or unsuccessful outcomes. Recently, together with the classical methods, conventional PMR methods and minimally invasive interventional therapies have often been applied in LDH treatment as a substitution of surgery or complementary treatment.

A technique to reduce herniated disc that is highly distressing or dysfunctional has been researched for many years. Percutaneous methods have been formulated to remove or diminish the herniated discal tissue, the fundamental rule being that it directly affects the herniated discal tissue without entering the spinal canal. The principal aim in such applications is hindering the probability of scar tissue formation in the epidural space, which results in the nerve tissue to comply with the moving bones and squeeze. Therefore, chondrolytic enzymes, hydrocortisone, papain, collagenase, or aprotinin injections are administered. However, the outcomes were insufficient and there were critical side effects despite the fact that each of these techniques was often utilized in specific periods [15, 16].

There are many studies on various points and potential explanations for the plate problem. Studies on distress from this issue have indicated that it might be the consequence of biochemical mechanisms that result in acid intoxication of the nerve. It has been related to an autoimmune response or ischemia that delivers a chronic inflammatory response which thus creates an acidic environment free of mechanical issues. These issues can be explained with biochemical medicines, diminishing the requirement for surgical methods.

Hence, today OT is utilized in various branches with various signs. It began to be utilized as an extra treatment in patients who do not react to conservative methods or a choice before surgical procedure to initiate anti-inflammatory, antioxidative capacity and immunomodulation effects in inflammatory and degenerative diseases associated with the musculoskeletal system, specifically LDH. It began to be utilized to profit from the immunomodulation effects and as the complications rate decreases, OT is increasingly more often applied in LDH patients because it is easy to use compared to the surgical method and the other techniques stated above [17]. Clinical studies assessing the effects of ozone on the musculoskeletal system are expanding as well. In this study, we retrospectively assessed the effect of paravertebral ozone injection treatment on distress and everyday life in patients with LDH.

2. Materials and methods

2.1 Patient population

We retrospectively assessed the records of 432 patients who had L4-5 and L5-S1 LDH diagnosed using a physical examination and magnetic resonance imaging. The patients were accepted to the PMR clinic for low back pain between May 2019 and March 2020 after the study was approved by the Institutional Review Board of our hospital (number: IRB 05-2020-001, date: 05.05.2020). The study included 358 patients whose records were assessed and who met the inclusion criteria. Of them, 60 patients who fulfilled the inclusion criteria were excluded from the study since they did not have the third month controls. Patients were recruited from our hospital’s physical therapy and rehabilitation outpatient clinics. The patients were provided with information regarding the study and they provided written informed consent. The individual rights of the patients were observed and the study was conducted in accordance with the Declaration of Helsinki. Although the study was retrospective, we strived to compare identical patients.

2.2 Inclusion and exclusion criteria

The patients were aged between 18 and 70, diagnosed with L4-L5, or L5-S1 LDH (at the level of protrusion) based on the MR result, and had LDH symptoms that were observed at a minimum of three months. Patients with a history of lumbar spine surgery, presence of lumbar spine diseases apart from LDH (piriformis syndrome, infection, spondylosis; spondylolysis, spondylolisthesis, ankylosing spondylitis; spinal stenosis, facet syndrome, spinal malignancy, osteoporosis), critical neurological loss, pregnancy, diabetes mellitus, or patients exercising for LDH were not included in the study.

Table 1
The demographic and clinical features of all patients

	Min-Max	Median	Mean $\pm$ SD/n-%
Age	18.0–69.0	44.0	44.71 $\pm$ 12.90
Gender
Female			144	48.3%
Male			154	51.7%
Duration of symptoms (months)	2.0–24.0	6.0	8.7 $\pm$ 5.4
LDH stage
L4-5			117	39.3%
L5-S1			181	60.7%
VAS
Before treatment	2.0–9.0	6.0	5.6 $\pm$ 1.7
After treatment	1.0–8.0	2.0	3.0 $\pm$ 1.7
3 months	0.0–9.0	2.0	2.9 $\pm$ 2.2
Oswestry disability index
Before treatment	6.0–78.0	26.0	29.5 $\pm$ 13.8
After treatment	2.0–58.0	15.0	16.9 $\pm$ 9.6
3 months	1.0–59.0	16.0	17.9 $\pm$ 12.4

Min: minimum, max: maximum, SD: standard deviation; LDH: lumbar disc hernia, VAS: visual analog scale.

2.3 Procedure

The patients received hot packs sized 40 $\times$ 30 cm (study group ( $n=$ 139), control group ( $n=$ 159)) as a superficial heat modality, in the face-down position for 20 minutes on the lumbar area. Conventional transcutaneous electrical nerve stimulation (TENS) application, with a frequency of 100 Mhz, 300 $\mu$ s stimulation time as an electrotherapy modality was carried out placing electrodes on the distressed area for 20 minutes through the usage of 5 $\times$ 5 cm sized plate electrodes in the face-down position. Ultrasound (US) was utilized as a deep heat modality at a frequency of 1 MHz, at a dosage of 1.5 watts/cm ${}^{2}$ , with a 5 cm ${}^{2}$ coil and for five minutes. TENS and US were applied using combined electrotherapy gadgets. This specific conventional physiotherapy program was carried out in 45 minute sets a day, five days a week, with 15 sessions in total. An OT injection was very steadily performed under sterile circumstances and two days a week with six sets in total to the 2.5 cm right and left side of the upper end of the spinous process of the vertebrae on the problem disc using a 22 gauge spinal needle for each area at 10 mL, 20 $\mu$ g/mL concentrations. Ozone injection was applied 2.5 cm deep, targeting the paravertebral muscle tissue. A cooling spray was utilized to avoid distress pre-application and the OT injections were applied to all patients by the same specialist doctor. In both groups, the VAS score for distress and ODI score for disablement were evaluated pre-treatment, at the end of treatment, and three months after the treatment ended when the patients were determined as control. The physiotherapist who applied physiotherapy and did not know whether ozone was applied to the patient or not, made the outcome measurements before and after the treatment and was blinded to the researcher who injected ozone. In addition, the demographic patient characteristics (age, gender, duration of symptoms, and MR-determined LDH level) were documented.

2.4 Evaluation criteria

2.4.1 Evaluation of distress

The participants’ severity of distress in the lumbar area was evaluated using VAS, a 10 cm horizontal scale scored from 0 (no distress) to 10 (very intense distress). The participators were requested to state the intensity of their distress and their responses were evaluated in cm and recorded.

2.4.2 Evaluation of the level of disablement

The level of disablement was ascertained with ODI. This questionnaire comprised of ten questions with an aim to evaluate the limitations faced by the patients in numerous activities in their everyday lives. There were six items, each item was between 0 and 5 points and the participant was asked to select the most convenient choice. The total raw score acquired was multiplied by two and conveyed in percentages. The items were: minimal (0–20%), moderate (21–40%) and severe functional impairment (41–60%) and disabled (61–80%). A score between 81% and 100% was considered to be either inexactly stated or the symptoms were exaggerated [18]. The Turkish validity and reliability in LDH patients were performed by Yakut et al. [19].

2.4.3 Data analysis

The descriptive statistics were expressed in mean, standard deviation, median; minimum, maximum value frequency, and percentage. The distribution of variables was checked using the Kolmogorov-Smirnov test. The Mann-Whitney U test was utilized to compare quantitative data. Wilcoxon test was used for the repeated measurement analysis. The qualitative data were compared with the Chi-square test. The Kaplan-Meier was utilized in the survival analysis. The SPSS 26.0 software package program was used for statistical analyses. The standard effect size was determined as 0.34 with 5% margin of error (a $=$ 0.05), 80% power. Therefore it was sufficient to enroll $n=$ 132 patients in each group. However, we randomly recruited all patients who met the inclusion criteria retrospectively, so 159 patients in one group and 139 patients in the other group were examined.

3. Results

Of the patients, 48.3% ( $n=$ 144) were female and 51.7% ( $n=$ 154) male. Their mean age was 44.71 $\pm$ 12.90. The length of the symptoms was mean 8.7 $\pm$ 5.4 months. LDH was found at L4-5 level 39.3% ( $n=$ 117) of the individuals and at L5-S1 level in 60.7% ( $n=$ 181). The mean VAS and ODI scores pre-treatment were 5.6 $\pm$ 1.7 and 29.5 $\pm$ 13.8. The third month VAS and ODI scores were 2.9 $\pm$ 2.2 and 17.9 $\pm$ 12.4, respectively. The demographic and clinical characteristics of all individuals are presented in Table 1.

The physiotherapy and physiotherapy $+$ OT groups did not have significantly different age and gender distribution and LDH stage ( $p>$ 0.05). The length of symptoms in the physiotherapy group was significantly higher ( $p<$ 0.05) than the physiotherapy $+$ OT group (Table 2).

Both groups did not have significantly different VAS and ODI scores prior to treatment ( $p>$ 0.05). In both groups, post-treatment third month VAS and ODI scores reduced significantly ( $p<$ 0.05) compared to pretreatment. In the physiotherapy $+$ OT group, the post-treatment third month VAS and ODI scores were significantly lower ( $p>$ 0.05) than the physiotherapy group (Table 2).

The groups did not have significantly different ODI degrees before treatment ( $p>$ 0.05). In the physiotherapy $+$ OT group, the third month ODI degree after treatment was significantly lower than the physiotherapy group ( $p<$ 0.05). In the third month after treatment, 75.5% ( $n=$ 105) of the physiotherapy $+$ OT group and 35.2% ( $n=$ 56) of the physiotherapy group regressed to stage 1 ODI (Table 3).

Table 2
Comparison of demographic characteristics, VAS and ODI scores between groups

		Physiotherapy		Physiotherapy $+$ ozone
		Mean $\pm$ SD/n-%	Median	Mean $\pm$ SD/n-%	Median	$p$
Age		45.3 $\pm$ 12.5	44.0	44.0 $\pm$ 13.3	44.0	0.403m
Gender	Female	79	49.7%	83	59.7%
	Male	80	50.3%	56	40.3%	0.083 ${}^{X^{2}}$
Duration of symptoms (months)		9.4 $\pm$ 5.1	9.0	7.9 $\pm$ 5.7	6.0	0.000m
LDH stage	L4-5	61	38.4%	56	40.3%	0.735 ${}^{X^{2}}$
Stage	L5-S1	98	61.6%	83	59.7%
Vas
Before treatment		5.5 $\pm$ 1.7	5.0	5.8 $\pm$ 1.6	6.0	0.187m
After treatment		3.8 $\pm$ 1.7	4.0	1.9 $\pm$ 1.1	2.0	0.000m
3 months		4.5 $\pm$ 1.8	5.0	1.0 $\pm$ 0.8	1.0	0.000m
Difference with before treatment
After treatment		$-$ 1.7 $\pm$ 1.5	$-$ 1.0	$-$ 3.8 $\pm$ 1.7	$-$ 4.0	0.000m
Intra group difference		0.000 w		0.000 w
3 months		$-$ 1.0 $\pm$ 1.5	$-$ 1.0	$-$ 4.7 $\pm$ 1.8	$-$ 5.0	0.000m
Intra group difference		0.000 w		0.000 w
Oswestry disability index
Before treatment		28.6 $\pm$ 13.5	26.0	30.4 $\pm$ 14.2	26.0	0.522m
After treatment		19.9 $\pm$ 10.5	16.0	13.6 $\pm$ 7.2	12.0	0.000m
3 months		24.7 $\pm$ 12.2	24.0	10.3 $\pm$ 7.0	6.0	0.000m
Difference with before treatment
After treatment		$-$ 8.7 $\pm$ 13.1	$-$ 8.0	$-$ 16.9 $\pm$ 15.1	$-$ 16.0	0.000m
Intra group difference		0.000 w		0.000 w
3 months		$-$ 3.9 $\pm$ 10.5	$-$ 3.0	$-$ 20.2 $\pm$ 16.0	$-$ 18.0	0.000m
Intra group difference		0.000 w		0.000 w

${}^{\text{m}}$ Mann-Whitney U test, $X^{2}$ Chi-square test, ${}^{\text{w}}$ Wilcoxon test.

Table 3

Comparison of ODI degrees between groups

	Physiotherapy		Physiotherapy $+$ ozone
	$n$	%	$n$	%	$p$
ODI before treatment
I	44	27.7%	31	22.3%	0.569 ${}^{X^{2}}$
II	81	50.9%	73	52.5%
III	32	20.1%	31	22.3%
IV	2	1.3%	4	2.9%
ODI after treatment
I	89	56.0%	95	68.3%	0.019 ${}^{X^{2}}$
II	65	40.9%	44	31.7%
III	5	3.1%	0	0.0%
ODI 3 months
I	56	35.2%	105	75.5%	0.000 ${}^{X^{2}}$
II	84	52.8%	34	24.5%
III	19	11.9%	0	0.0%

${}^{X^{2}}$ Chi-square test, ODI: Oswestry Disability Questionnaire.

4. Discussion

This study aimed to examine the effects of OT injection on distress and functional condition in those with LDH in the short and medium-term. The present study found a significant advancement in VAS and ODI scores in the controls after treatment and in the third month compared to the group receiving physiotherapy, which we identified as the control group in the OT injection group.

Low back pain is an unpleasant symptom that can be observed in 70 to 80% of people at some point in their lives [20]. In 60 to 70% of the cases, low back pain results from mechanical strains and degenerative diseases of the spine [21]. In contrast to the estimations, LDH does not frequently cause low back pain. Nevertheless, it is clinically significant since it limits daily life activities by causing severe pain and neurological losses. Additionally, because LDH is usually seen in people aged under 50 and is more commonly observed in men, the loss of the labor force of active people in this age demography also results in socioeconomic issues [22]. The mean age of LDH patients was 44.71 $\pm$ 12.90 and the male ratio was higher, which is in line with the literature. LDH is mostly in the regions of L5-S1 (40.9%), then L4-L5 (38.0%) and L3-L4 (19.1%), respectively [23]. Our study was in line with this data. With aging and repetitive forced moves, the intervertebral disc undergoes biochemical and biomechanical changes such as the water loss in the nucleus pulposus and augment in the polysaccharide complex and collagen structure, and thus disc herniation is observed [24]. In LDH, distress is seen due to mechanical pressure resulting from the disorder of the endoneurial blood flow and/or chemical irritation of proteoglycans sourcing from the ruptured disc and causing intraneural inflammation. This inflammatory reaction is identified by edema, inflammatory cell infiltration, and local demyelination. So, the spinal nerve becomes hypersensitive to mechanical stimuli and causes radicular distress and paresthesia symptoms [25]. Apart from the mechanical irritation of the nociceptors in the annulus fibrosus, chemical alterations in the degenerated disc also affect discogenic distress. Prostaglandin E, substances similar to histamine, potassium ion; lactic acid, and various polypeptide amines in interstitial fluid prompt primary sensory neurons or diminish the excitation threshold [26]. The studies assessing the efficiency of OT in low back pain associated with disc herniation report that ozone decreases distress pain in the long-term if it’s applied to the disc or paravertebrally. Ozone is an unstable, strong oxidizing gas with antiseptic, immunomodulating, analgesic, and anti-inflammatory properties consisting of three oxygen atoms [27, 28]. It was firstly used in medicine by Fisch in 1932. The use of OT increases every day in musculoskeletal diseases resulting from reduced inflammation, quick control of distress, and related early mobilization effects [29, 30]. Many studies found that ozone had curative effects. If there is nerve root compression, ozone may have an anti-inflammatory effect, enhanced tissue oxygenation and oxidation of algogenic substances, in lost or reduced nerve root pressure by dehydration of overflowed or herniated disc tissue. To date, studies have hypothesized that OT injection, a strong oxidant, stimulates excess production of superoxide dismutase, catalase, and other antioxidant enzymes that counterbalances the formation of dense reactive oxygen species. Following intradiscal and intramuscular paravertebral injection, ozone can expedite the degradation of proteoglycans in the degenerate nucleus pulposus, and result in reabsorption and dehydration, which accordingly leads to decreased herniated material prompting nerve root compression [17].

Intradiscal OT is administered as an injection with the aid of radiological imaging (computed tomography (CT), fluoroscopy) when the patient is sedated. Immediate oxidative stress that happens when ozone is provided to the nucleus pulposus or inflamed joint spaces prompts an antioxidant reaction. Such a reaction is observed due to the cholinergic anti-inflammatory route and it supplies both mechanical decrease in disk size and a biochemical diminution of the inflammation [31, 16]. Indicators of intradiscal OT are identical with surgical indicators and thereby it is one of the pre-operation treatment alternatives that can be carried out.

Paravertebral intramuscular OT injections are easy and common applications. We can differentiate this technique as a classic paravertebral for one thing and deep paravertebral applications for another. In the classical paravertebral procedure, which is the technique we used, 2.5 cm right and left side of the upper end of the spinous process of the level above the problem disc 5–10 mL gas mixture for each area is administered very slowly, at maximum concentrations of 20–25 $\mu$ g/mL [31]. Bocci called this technique chemical acupuncture. The deep paravertebral technique is injected at the identical doses and concentrations, 1.5 cm from the midline in the cervical and dorsal, injected in the lumbar 2 cm to the right and left deeper, to the periarticular area. The injection should be performed gradually and with a thin needle. Concentrations above 20–25 $\mu$ g/mL can be considerably distressing. The injection can be performed with local anesthetic or cold application for the management of distress [31]. In our study, in line with the literature, we very slowly applied the mixture 2.5 cm to the right and left side of the upper end of the spinous process of the vertebrae on the problem disc, using a 22 gauge spinal needle 10 mL, 20 $\mu$ g/mL concentrations under sanitary circumstances. We also used a cooling spray to avoid distress before the application.

In a meta-analysis assessing the efficiency of percutaneous OT injection in individuals with low back pain due to disc herniation performed by Magalhaes et al., eight observational and four randomized studies were examined. The level of proof for long-term distress diminution was II-3 for intradiscal and II-1 for paravertebral applications. Based on the recommended rating, intradiscal ozone is 1C and paravertebral ozone is suggested as 1B. In this meta-analysis, “percutaneous ozone administration in individuals with ongoing low back pain, seems to be a treatment with positive outcomes and a very low morbidity rate” [32]. In their study, Zhang et al. randomly divided 172 adult patients with low back and radicular pain into two groups: intradiscal and intraforaminal. OT injections were applied to 90 patients and apart from this treatment, 1 ml of betamethasone compound were injected into the other 82 patients. Although there was significant progress in back pain levels in both groups at the sixth and 12 ${}^{\text{th}}$ month controls, a significant difference was not found between the groups. Therefore, ozone nucleolysis supplied prime pain ease for most people who suffered from a herniated disc and did not respond to conservative methods. However, there was no difference between ozone and the combined steroid injection at the sixth and 12 ${}^{\text{th}}$ months. Hence, ozone application should be the primary choice without the requirement for pre-operative epidural steroid infiltration, or in case a surgical procedure is not possible as ozone can aid the management of distress [33].

A study was carried out by Lehnert et al. on the treatment of LDH under BT instruction, intradiscal and periganglionic injections in 2012 to determine before and after injection disc volumes. 283 patients with LDH were injected with a single dose of intradiscal (3 mL) and periganglionic (7 mL) ozone (ozone concentration 30 $\mu$ g/mL) where disc volume alterations were evaluated with BT six months later.

With in-disc OT injection, significant decreases in herniated disc volumes were determined [34]. In their randomized placebo-controlled study carried out to evaluate the efficiency of paravertebral intramuscular OT injection in LDH patients who did not respond to conservative methods, Paoloni et al. found a significant difference in decreased back pain in the sixth month control of 60 LDH patients with acute low back pain, compared to placebo [35]. In a study contrasting lumbar paravertebral OT injection with nonsteroidal anti-inflammatory drugs in those with L4-L5 or L5-S1 disc herniation, a significant difference was observed in the distress level of the injection group compared to the group using anti-inflammatory drugs and this difference persisted in the third and sixth month follow-up from the second week after treatment. Nevertheless, there was no significant difference between the two groups’ MR findings and electromyography was performed in the sixth month follow-up [36]. There are nearly no side effects of OT applied at convenient doses. The majority of the side effects mentioned up until now are local complications resulting from application mistakes. In our study, none of the individuals who received ozone had complications.

5. Conclusions

To conclude, paravertebral OT injection is a highly safe and beneficial management technique for those with LDH. This method can be more profitable if it is used in the assistance of conservative methods. We think that this study will contribute to the literature considering that there is a very small number of publications on paravertebral OT injections and further multicenter, placebo-controlled studies examining the extended effects of OT injections should be conducted. Our study has some limitations. It was not a placebo-controlled study and the extended effects of the treatment were not examined. Additionally, this was a retrospective study.

Footnotes

Conflict of interest

None of the authors have any conflict of interest to declare.

References

Oğuz

Dursun

, Tıbbi Rehabilitasyon, Nobel Tıp Kitapevi, 1146-1150.

Parisini

Di Silvestre

Greggi

Miglietta

Paderni

. Lumbar disc excision in children and adolescents. Spine. 2001; 26: 1997-2000.

Lee

Ernestus

Schroder

Klug

. Histological study of lumbar intervertebral disc herniation in adolescents. Acta Neurochir (Wien). 2000; 142: 1107-1110.

Sarı

Aydoğan

. Bel ağrısının önemli bir sebebi: Lomber disk hernisi. TOTBİD Dergisi. 2015; 14: 298-304.

Vialle

Suárez Henao

Giraldo

. Lumbar disc herniation. Rev Bras Ortop. 2015; 45(1): 17-22.

Soysal

Kara

Arda

. Assessment of physical activity in patients with chronic low back or neck pain. Turk Neurosurg. 2013; 23(1): 75-80.

Jordan

Konstantinou

O’Dowd

. Herniated lumbar disc. BMJ Clin Evid. 2011; 6: 1118.

Jansson

Nemeth

Granath

Jönsson

Blomqvist

. Health-related quality of life in patients before and after surgery for a herniated lumbar disc. J Bone Joint Surg. 2005; 87(7): 959-964.

Evcik

. Kronik bel ağrılı hastalarda depresyon ve yaşam kalitesi. Yeni Tıp Dergisi. 2008; 25: 228-231.

10.

Ökmen

Koyuncu

Uysal

Özgirgin

. The effects of the number of physical therapy sessions on pain, disability, and quality of life in patients with chronic low back pain. Turk J Med Sci. 2017; 47(5): 1425-1431.

11.

Belavý

Quittner

Ridgers

Ling

Connell

Rantalainen

. Running exercise strengthens the intervertebral disc. Sci Rep. 2017; 7(19): 45975.

12.

Vanti

Andreatta

Borghi

Guccione

Pillastrini

Bertozzi

. The effectiveness of walking versus exercise on pain and function in chronic low back pain: a systematic review and meta-analysis of randomized trials. Disabil Rehabil. 2019; 6(41): 622-632.

13.

Jegede

Ndu

Grauer

. Contemporary management of symptomatic lumbar disc herniations. Orthop Clin North Am. 2010; 41(2): 217-224.

14.

Jacobs

van Tulder

Arts

Rubinstein

van Middelkoop

Ostelo

, et al. Surgery versus conservative management of sciatica due to a lumbar herniated disc: a systematic review. Eur Spine J. 2011; 20(4): 513-22.

15.

Vaquero

Martinez

Saucedo

Brasa

Bujan

. Intradiscal aprotinin in lumbar disk bulging. Surg Neurol. 1989; 31(3): 245.

16.

Intradiscal Injection of O2-O3 to Treat Lumbar Disc Herniations. Alexandre

Buric

Paradiso

Saldago

Murga

Cor

Albarreal

Scopetta

Giocoli

Marin

. Rivista Italiana di Ossigeno-Ozonoterapia. 2002; 1: 165-169.

17.

Bocci

. Biological and clinical effects of ozone. Has ozone therapy a future in medicine? Br J Biomed Sci. 1999; 56(4): 270-279.

18.

Hazer

Acarbaş

Rosberg

. The outcome of epiduroscopy treatment in patients with chronic low back pain and radicular pain, operated or non-operated for lumbal disc herniation: A Retrospective Study in 88 Patients, Korean J Pain. 2018; 31(2): 109-115.

19.

Yakut

Düger

Oksüz

, et al. Validation of the Turkish version of the Oswestry Disability Index for patients with low back pain. Spine. 2004; 29(5): 581-585.

20.

Oğuz

. Bel ağrıları, Oğuz H (Editör). Tıbbi rehabilitasyon’da. İstanbul: Nobel Kitapevleri, 2004, pp. 1131-71.

21.

Müslümanoğlu

. Bel ağrısının nedenleri. Özcan E (Editör). Bel ağrısı tanı ve tedavisi’nde. İstanbul: Nobel Kitabevi, 2002, pp. 147-77.

22.

Kırış

Turantan

, Lomber disk hastalığı ve cerrahi tedavisi. Fiz Tıp ve Reh Derg. 1998; 1(1): 85-90.

23.

Dammers

Koehler

. Lumbar disc herniation: level increases with age. Surg Neurol. 2002; 58(3-4): 209-212.

24.

Karacan

, Rezvani A. İntervertebral diskte dejenerasyon sürecinin lomber disk hernisi gelişiminde rolü. Fiz Tıp ve Reh Derg 2001; 47(5): 12-15.

25.

Barr

Harrast

. Low back pain. In: Braddom

(Ed.). 4th ed. Physical medicine and rehabilitation. Philadelphia: Saunders, 2007, pp. 883-927.

26.

Berker

. Belde ağrı kaynakları. Özcan E (Editör). Bel ağrısı tanı ve tedavisi’nde. İstanbul: Nobel Kitabevi, 2002, pp. 45-933.

27.

Haug

, Heidelberg Rilling

Viebahn

. The use of Ozone in Medicine, classical medical ozone textbook. 11 edition 1987.

28.

Bocci

. Autohaemotherapy after treatment of blood with ozone. A reappraisal. J Int Med Res. 1994; 22(3): 131-144.

29.

Zhou

Cheng

. Treatment of middle-aged and aged patients with knee osteoarthritis of yang-deficiency induced cold-damp syndrome by ozone combined Chinese materia medica: a clinical research. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013; 33(4): 471-475.

30.

Daif

. Role of intra-articular ozone gas injection in the management of internal derangement of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012; 113(6): 10-14.

31.

Alexandre

Buric

Paradiso

. Intradiscal injection of O2-O3 to treat lumbar disc herniations: Results at five years. Rivista Italiana di Ossigeno-Ozonoterapia. 2002; 1: 165-169.

32.

Magalhaes

Dotta

Sasse

Teixera

Fonoff

. Ozone therapy as a treatment for low back pain secondary to herniated disc: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2012; 15(2): 115-129.

33.

Zhang

Jiang

Ding

Wang

. Treatment of the lumbar disc herniation with intradiscal and intraforaminal injection of oxygen-ozone. J Back Musculoskelet Rehabil. 2013; 26(3): 317-322.

34.

Lehnert

Naguib

Wutzler

Nour-Eldin

Bauer

Kerl

, et al. Analysis of disk volume before and after CT-guided intradiscal and periganglionic ozone-oxygen injection for the treatment of lumbar disk herniation. J Vasc Interv Radiol. 2012; 23(11): 1430-1436.

35.

Paoloni

Di Sante

Cacchio

Apuzzo

Marotta

Razzano

, et al. Intramuscular oxygen-ozone therapy in the treatment of acute back pain with lumbar disc herniation: a multicenter, randomized, double-blind, clinical trial of active and simulated lumbar paravertebral injection. Spine (Phila Pa 1976). 2009; 34(13): 1337-1344.

36.

Melchionda

Milillo

Manente

Stoppino

Macarini

. Treatment of radiculopathies: a study of efficacy and tollerability of paravertebral oxygen-ozone injections compared with pharmacological anti-inflammatory treatment. J Biol Regul Homeost Agents. 2012; 26(3): 467-474.