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THIRD PARTY CLINICAL STUDIES / NEXT GENERATION PDT

CLINICAL STUDY: PROSTATE CANCER TREATED BY NEXT GENERATION PDT

STUDY BY: Dr Donald Murphy 1,2, Dr Brian Meade 3, Dr Avni Sali 3.
LOCATIONS: Geelong Private, St John of God & Colac Hospitals 1, Skills Laboratory RACS. Melbourne2, National Institute of Integrative Medicine Melbourne3.

 

Introduction This phase 1 ethics approved trial has been established to assess the potential role of Sono and Photo-dynamic Therapy using Radachlorin, Sonnelux and Photosoft sensitisers in a cohort of 66 patients, across a range of biopsy-proven prostate cancer patients. Including patients with focal disease who are under surveillance and also patients with persisting cancer, after radical treatments. History of Light Therapy 1903 Nobel Prize N. Finsen – Light therapy. 1904 Von Tappeiner - PD reaction first shown. 1925 Nobel Prize H. Fischer – Porphyrins. 1942 Porphrins – First used in treatments 1958 Light Bed therapy for Neonatal Jaundice. 1971-85 Dougherty – Photofrin therapy. Russian and Chinese PDT developments Western interest in PDT applications. 1990 Windahl et al. – PDT for local prostate cancer. 2006 Moore & Emberton. – Interstitial PDT. Aim To investigate the role of sono and photo-dynamic therapy in the treatment of prostate cancer. Method The sensitiser is taken sub-lingual or orally 16-24 hours before each treatment cycle. The laser and ultrasound probes provide the energies which are directed at the prostate in a combination of trans-rectal, trans-urethral and per-cutaneous techniques. Energy delivered AM and PM each day.(25 min max.) for 3 days over one week and then repeated twice in 12 weeks. Laser red light at a maximum of 2 watt at 4000-5500 Joules. Ultrasound set to a maximum of 1 watt and at low frequency. The treatment is performed as an Outpatient procedure with eye protection provided. Picture 1: Experimental proof of trans-rectal illumination in a pig model. Picture 2 & 3: Prostate speciment with & without illumination.

Results For 26/40 patients now treated for > 6 months. The dosage of the sensitisers as well as the spectral range of the two energies used, have been shown to be safe. There have been no safety issues. The sensitisers used have displayed no systemic toxicity or sun sensitivity. The interim results are as follows:- 1. The flow studies, IPSS profile and Quality of Life due to urinary symptoms, recorded low scores as improved or unchanged except for one patient. 2. The PSA patient data for > 6 months post treatment :- (a). stable or decreasing in 13/26. (b). Increasing in 8/13 (neg. Bone/CT scans) with a positive prostate biopsy and 3/13 a negative biopsy. (c). Increasing PSA (positive lymph nodes on Abd. CT) in 2/13. 3. UTI In 2 patients, cleared on treatment. 4. No urinary incontinence or rectal injuries. 5. One 79 year old patient with increasing obstructive urinary symptoms was treated by TURP. 6. Decreasing prostate size on assessment. (DRE, Ultrasound & MRI) 7. No alteration in erectile function. Conclusions The phase 1 criteria have been met regarding the sensitiser doses and equipment safety. Normal bladder and bowel function, as well as unaltered potency have been recorded. A stable or decreasing PSA has been recorded in 13/26 patients . An apparent / proven decrease in prostate size (ref.1) has been noted. This experimental treatment may have a future in the management of prostate disease. References 1.Moore, C. M., Emberton, M. and Bown, S. G. (2011), Photodynamic therapy for prostate cancer-an emerging approach for organ-confined disease. Lasers in Surgery and Medicine, 43: 768-775. doi: 10.1002/lsm.21104 Acknowledgements I wish to record my gratitude to the Companies supplying the agents and also the relevant equipment. I also record my thanks to Paul Fargher at Geelong Physiotherapy for providing his Ultra-sound equipment. There has been no financial payment by the companies for this study.

 

Consultant to research project using ozone to shrink displaced disks between vertebrae in the back to eliminate  pain caused by the expanded disk pressing on the nerve:

CT-guided ozone nucleolysis (ONL) in the management of back pain and sciatica

George Koulouris1,2 MBBS, GrCertSpMed, MMed (Radiol) FRANZCR

Ojas Hrakesh Mehta,1 MBBS, BMedSci

1. Melbourne Radiology Clinic, 100 Victoria Pde, East Melbourne, 3002, Victoria, Australia

2. Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Nedlands 6009, WA, Australia

Introduction

Back pain is an enormous clinical, social and economic problem, with up to 85% of adults experiencing back pain at some stage during in their lifetime.1 Chronic low back pain has many causes that can generally be divided into degeneration of the intervertebral discs (39-42%), facet joints (31%) and sacroiliac joints (18%).2,3 Although disc disease is implicated in all ages, sacroiliac and facet joint arthropathy are more frequently seen in older patients.2

Historically, after failed conservative treatment, surgical intervention has been the next therapeutic option. The Maine Lumbar Spine Study, where most patients in the surgical arm received open discectomies for lumbar disc herniation with sciatica, showed significant benefit of surgery over conservative management in patients with moderate or severe sciatica. This relative benefit of surgery unfortunately decreased over the five-year period studied,4 with a failure rate variably quoted between 10% and 40% (“Failed Back Surgery Syndrome”).5 Five-year re-operation rates are estimated at approximately 14%, with half occurring within the first post-operative year and success rates declining dramatically with every re-operation.

Since the 1980s, many minimally invasive percutaneous methods have been developed as a means of obviating surgical intervention, delaying surgery or decreasing the number of surgical interventions required. These minimally invasive interventions include percutaneous endoscopic or laser discolysis, intradiscal electrothermy (IDET) and chemonucleolysis. Studies involving these procedures have been mostly cohort studies and have limitations.15,16 Despite insufficient evidence for routine use, specific subgroups of patients have shown discernible benefit with these interventions.6 Ozone nucleolysis (ONL) has recently shown promise in a similar cohort/subset of patients who have failed conservative treatment and are keen to avoid surgery. It is also a minimally invasive injection therapy that is typically provided in an ambulatory/outpatient setting. ONL has the advantage that it can be used in both contained and non-contained herniations, unlike other percutaneous techniques, such as alcohol, chymopapain or thermal ablation, which can have deleterious effects upon adjacent neural structures.7

Intervertebral disc pathophysiology

As the intervertebral disc degenerates with age, fissures of the rigid outer annulus fibrosis occur, with secondary herniation of the nucleus pulposus. In the normal disc, only the outer annulus fibrosis receives sensory innervations; however, these nerves may penetrate deeper into the disc following annular degeneration and fissuring. The proteoglycan content of the nucleus, having not been exposed to the immune system after birth, triggers an autoimmune reaction,8 inducing pro-inflammatory mediators, which excite and sensitise nociceptors to bradykinin and other pain-producing substances. Further to this, non-immune mediated infiltration of histiocytes, local fibroblasts from the disc periphery and chondrocytes within the disc, result in the production of cytokines, interleukins 1 and 6 and tumour necrosis factor-alpha, ultimately leading into an accumulation of phospholipase A2, prostaglandin E2, matrix metalloproteinases and thromboxanes. These substances result in an inflammatory cascade which further sensitise local nerves as well as the dura and surrounding spinal nerves.8-10

Phospholipase A is an important mediator of radicular pain, which in itself is responsible for liberation of arachidonic acid. The inflammatory cascade results in increased tissue swelling, with secondary decreased arterial supply as well as increased venous and lymphatic stasis.7 The net ischaemic effect of decreased oxygen diffusion, increase in local lactate concentration and decrease in pH results in a vicious cycle of increased swelling and promotion of inflammation, which when it exceeds a certain threshold, results in direct mechanical compression of neural structures such as spinal nerves, small nociceptive fibres in the posterior annulus fibrosus, posterior longitudinal ligament and ventral dura that can all lead to chronic pain.11-13

Ozone mechanism of action

The unstable ozone molecule (O3) consists of three oxygen atoms covalently bonded to one another, with a molecular weight of 48 kDa. Ozone must be administered at non-toxic concentrations of 1-40 μg, where ozone has the paradoxical effect of inducing endogenous production of antioxidant enzymes in tissues without overcoming their antioxidant mechanisms. In excess of this, the antioxidant enzyme system is overwhelmed, with the result being accumulation of superoxide anion (O2-) and hydrogen peroxide, which can cause cell membrane degradation. Ozone dissolves in intradiscal water and quickly dissociates into an oxygen molecule (O2), thereby releasing an oxygen free radical. This free radical gives ozone its highly oxidizing property, upregulating intracellular antioxidant scavenger systems14 and neutralizing excessive reactive oxygen species. As such, ozone possesses powerful anti-septic properties, as well as immunomodulating, analgesic and anti-inflammatory characteristics. It exerts a direct effect on complex macromolecules, inducing degeneration of proteoglycans and glycosaminoglycans within the nucleus pulposus by disrupting their intra and intermolecular chains, leading to collapse of their three-dimensional structure. The degradation of these macromolecules releases entrapped water that is then reabsorbed, thereby dehydrating the disc and reducing its volume. This dehydration and loss of discal volume, with decreased mass effect upon surrounding structures, is felt to be the main mechanism of action by which ONL improves the symptoms of radiculopathy. The cellular degeneration of the matrix is then replaced by connective and activated fibroblasts within five weeks, causing additional scarring and further reduction of the herniated disc, with vacuole formation and fragmentation on histological examination, a process referred to as “disk mummification”.15 Extrinsic to the disc, ozone is known to have an immunomodulating effect, reducing the release and activation of inflammatory mediators such as cytokines, bradykinins, prostaglandins and other pain-producing substances. Ozone may also improve local oxygenation by increasing arterial afferent supply, venous and lymphatic stasis and reducing local acidosis.

Ozone nucleolysis injection technqiue

ONL involves the direct injection of a mixture of oxygen and ozone into the intervertebral disc, using either fluoroscopy or computed tomography (CT) for guidance. The mixture can also be injected into the epidural space, intervertebral foramen and paravertebral muscles to achieve a further “halo” analgesic effect, depending on the anatomic abnormalities on imaging, clinical findings, available scientific evidence and individual operator experience. Like any gas, the ozone injected during ONL is visualized as an area of lucency and is best seen with CT, where even the smallest gas locule of ozone can be detected. CT accurately demonstrates the pattern and extent of spread within the disc, achieving a discographic effect, as well as any spread external to the disc should it extend beyond it. CT also has the advantage of three-dimensional appreciation of needle position, improved appreciation of spread of the ozone gas in relation to surrounding anatomic structures, as well as decreased operator radiation exposure. Fluoroscopically guided ONL has been used with equal efficacy as when compared to CT and the techniques used to negotiate the needle into the disc are similar. Ultimately, determining which modality is used to perform ONL will vary with personal operator preference, experience and availability of the specific modality within the facility where the procedure is performed.

No specific preparation is required for ONL, with the procedure performed on an outpatient basis. Formal informed consent is obtained and the patient may be administered a light sedative and oral analgesics. Another alternative used at other institutions is to administer conscious sedation. At our institution, the patient is placed prone in the CT scanner (Emotion 16 slice Multi-detector CT, Siemens Medical systems, Erlangen, Germany) with a series of planning axial scans at 3 mm slices performed at the intervertebral disc level of proposed intervention. The intended needle trajectory is then planned from these images and the needle entry point marked on the skin. 5ml of 1% lignocaine is injected into the skin and subcutaneous tissues and thereafter, utilising a transforaminal approach, a 9 cm, 12.7 cm or 17 cm 22 g spinal needle is advanced into the affected disc under CT guidance at approximately 45-60º. As with any percutaneous disc injection, extreme care is taken to avoid contacting the exiting nerve root by visually following its path on the CT images during the procedure, as well as clinically monitoring the patient for any symptoms of leg pain. Once needle position in the disc has been confirmed (Figure 1A), a small amount of iodine contrast may be injected to outline the pattern of contrast spread, which typically predicts the spread of the ozone gas (Figure 1B). However, this step is often not performed and can be omitted. 5 cc of an oxygen-ozone mixture, prepared from room air using an ozone generator with a concentration of 30 μg/ml is injected (Figure 1B), at which point a set of three axial images is obtained (one above, one at and one below the level of injection). The needle is withdrawn to the level of the foramen, where contrast is injected (Figure 1C) so as to avoid any intravascular injection of ozone and to confirm epidural spread. Once confirmed, 2 cc of celestone chronodose, 5 cc of 1% lignocaine and a further 5 cc of ozone at a similar concentration as above are injected (Figure 1D). This technique is repeated for each level that requires treatment. The procedure is thus completed and the patient is rested in recovery bay for an hour and  typically discharged following this time frame without event. A week of rest is prescribed, with continuation of an analgesic regimen familiar to the patient. Following this, rehabilitation may commence and review with the referring clinician.

Contact us for copies of these images:

Figure 1A. Under CT-guidance, a 22 g spinal needle is negotiated into the periphery of the nucleus pulposus of the L4/5 intervertebral disc, approaching the disc from the left side. The centre of the nucleus pulposus is indicated by the arrow.

Figure 1B. Contrast is then injected, denoted by the hyperdense (white) fluid within the disc, followed by the ozone gas (hypodense, or dark material; long arrow). In this instance, gas is already seen in the epidural space, highlighting a focal left paracentral protrusion (short arrow).

Figure 1C. The needle is then withdrawn to the neural foramen and contrast injected, with its flow observed (arrow), confirming an extravascular position.

Figure 1D. A further dose of ozone is injected, with extension of the gas into the epidural space (long arrow) as well as the neural foramen and surrounding nerve root (small arrow).12

Ozone nucleolysis (ONL) efficacy

In a meta-analysis of 12 studies, ONL demonstrated an 80% likelihood of improvement in over 8,000 patients, similar to results seen in surgical discectomy, with a low complication rate of 0.06% and improved recovery time.16 Apart from the advantage of being minimally invasive, ONL minimises epidural fibrosis/scarring, is a quick and simple procedure, requires at most only light sedation and, where required, can be repeated numerous times at multiple levels. It is also of advantage in patients who pose an unacceptable anaesthetic risk. The comparable efficacy of ONL and microdiscectomy was further supported in a series of 45 patients with non-contained lumbar disc herniations. Twenty-seven patients (90%) in the ONL group showed a statistically significant improvement in pain and function that was similar to the microdiscectomy group (14 patients; 93.3%). Owing to “aggravating” symptoms, two patients from the ONL group underwent subsequent surgery.17 Similar success was noted between ONL and microdiscectomy cohorts, with patients proceeding emergently to microdiscectomy in the first instance only in the context of severe pain and/or neurological deficit.18

In an observational study of 2,900 patients, ONL and intraforaminal zone injections were effective for soft disc herniations (75-80%), multiple herniations (70%) and failed back surgery syndrome (55%), without complications.19 The same authors published similar results for 2,200 patients, with again high success rate of 80% at six months, which dropped slightly to 75% at 18 months. The failure rate was higher in patients with spinal canal stenosis, calcified herniated disk, recurrent herniation with epidural fibrosis and lateral recess herniation.20 Excellent results were also observed in a group of 600 patients, where a 78.3% success rate was noted in patients treated with ozone therapy and periganglionic steroid injection, compared with a 70.3% success rate in those treated with ozone therapy alone. In a group of 621 patients who were subjected to CT-guided ONL in combination with periradicular infiltration with steroids, the Oswestry Disability Index (ODI) and visual analog pain scale (VAS) were measured. In this study, it was observed that patients younger than 50 years had significantly better values on the VAS and in ODI scores.21 Combined ozone and steroid intradiscal and intraforaminal injections have been shown to be more effective (74% success rate at six months) than steroid alone (47%).22 ONL has also demonstrated an additional benefit when combined with radiofrequency ablation (RFA) of the nucleus pulposus (VAS of 26 for ONL/RFA combined, compared to 33 in ONL alone at 12 months; ODI of 21 and 26 for ONL/RFA and ONL alone respectively) and though an exciting combination of pain management procedures, this has only been reported in one study and further research is required.23 ONL has also been used with collagenase and shown to have comparable results to surgery.24

Other uses of ozone

In a randomised control trial, ozone injections into the neural foramen alone were shown to be of improved efficacy in the management of lower back pain and/or sciatica versus steroid injections alone at six months (74% versus 58%).25 Intramuscular paravertebral injections of ozone also resulted in a lower VAS (0.66) versus the control sham group (4.00) who received simulated therapy. Furthermore, 61% versus 33% of patients became pain free. Ozone therapy was also associated with a shorter period of non-steroidal anti-inflammatory therapy.26

Indications

Lumbar and radicular pain not responding to conservative treatment

Imaging features that account for/are concordant with the clinical presentation

Poor surgical candidate

Facet joints and paravertebral muscle spams

Contained and non-contained disc herniations

Multiple levels

Failed back syndrome

Contraindications

Pregnancy

Sepsis

Cauda equina syndrome

Worsening neurological/motor deficit

Migrated (sequestrated) disc fragment

Tumour

Fractures

Complications

Ozone therapy for lumbar disc herniation is a procedure that is safe, well tolerated and with a high success rate, making it appealing to patients as an alternative to surgery, or a palliating procedure where surgery has previously failed. Complications are fortunately rare, with minimal, or no, adverse effects at concentrations used for therapeutic application (10-40 μg/mL). General complications not specific to ozone but common to all percutaneous injections include septic complications such as cellulitis, discitis, epidural abscess and septicaemia.27 The use of pre-procedural antibiotics as well as using a co-axial needle technique are means by which the septic complication rate may be decreased, though this is a known contentious issue in discography. It has been postulated that the disinfecting properties of ozone may decrease the chances of septic complications following percutaneous ONL.28 It is postulated that microfractures within the disc may communicate with the spinal canal and thecal sac, resulting in transient though rapid increases in CSF pressure and thus account for rare neurological complication such as blindness (due to bilateral vitreo-retinal haemorrhages,29 stroke30 and nerve trauma,31 though the latter may also occur due to direct needle trauma and/or post-injection haemorrhage/haematoma. The development of acute thunderclap headache32 has been known to occur due to pneumocephalus as a consequence of inadvertent puncture of the thecal sac. Though not a complication per se, exacerbation of pain is a known issue following the procedure that typically settles within several days and requires rest, avoidance of exacerbating activities and analgesia.

Criticisms of ozone-based percutaneous therapies

Many ONL and non-intradiscal ozone spine injection studies to date have included heterogeneous patient groups with the diagnosis of “back pain/lumbago” or “sciatica” and for which a broad range of treatments have been prescribed. Most studies have compared ONL injections, with or without periradicular/foraminal cortisone and/or ozone injection, as well as paravertebral injections of ozone. Further to this, few studies have performed follow-up CT and/or MRI examinations documenting the resolution/improvement of disc pathology occurring in conjunction with clinical improvement. Admittedly, this may be time consuming in practice and adds expense to patient management. Naturally, given the proposed mechanism of ONL, ozone therapy works first and foremost at the cellular level, reducing inflammation and therefore potentially resulting in clinical resolution of symptoms with decreasing disc volume. Hence, many patients may improve simply on the basis that the inflammatory component of their back pain has resolved, despite unaltered disc volume.

The current approach at our institution has been with an open mind when it comes to ozone-guided therapies. As it is a promising technique with minimal complications and is currently finding broad applications, many clinicians and patients are keen to trial ONL as a primary treatment, following failed cortisone injections, as a palliative procedure or as a final procedure in an attempt to avoid surgery. Hence, we see a heterogeneous group of patients in whom ozone has been injected with great success; however our success thus far has been anecdotal. We do not feel it unreasonable to use ozone in similar indications as one would use cortisone (for example, an epidural or intraforaminal/periradicular injection) and obviously where a concomitant disc herniation or bulge is present, then ONL can be performed in the same sitting. In our experience, we have found this technique has worked the best. We do not perform ozone paravertebral muscle injections, namely because this has never been referred to us and also possibly due to the fact that, where this is being performed, the procedure is performed clinically and thus radiological guidance is not required.

References

1. Schmidt CO, Raspe H, Pfingsten M et al. Back pain in the German adult population: prevalence, severity, and sociodemographic correlates in a multiregional survey. Spine 2007; 32: 2005-2011.

2. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med 2011; 12: 224-233.

3. Schwarzer AC et al .The relative contributions of the disc and zygapophyseal joint in chronic low back pain. Spine 1994; 19: 801-806.

4. Atlas SJ, Keller RB, Chang Y et al. Surgical and nonsurgical management of sciatica secondary to a lumbar disc herniation: five-year outcomes from the Maine Lumbar Spine Study. Spine 2001: 26: 1179-1187.

5. Chan CW, Peng P. Failed back surgery syndrome. Pain Med 2011; 12: 577-606.

6. Staal JB, de Bie R, de Vet HC et al. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev 2008; 16: CD001824.008.

7. Andreula C, Muto M, Leonardi M. Interventional spinal procedures. Eur J Radiol 2004; 50: 112-119.

8. Burke JG, Watson RW, McCormack D et al. Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br 2002; 84: 196-201.

9. Kang JD, Georgescu HI, McIntyre-Larkin L et al. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 1996; 21: 271-277.

10. Chang J, Gilman SC, Lewis AJ. Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: a possible signal for IL 1 action. J Immunol 1986; 136: 1283-1287.

11. Vanharanta H, Sachs BL, Spivey MA et al. The relationship of pain provocation to lumbar disc deterioration as seen by CT/discography. Spine 1987; 12: 295-298.

12. Kallewaard JW, Terheggen MA, Groen GJ et al. 15. Discogenic low back pain. Pain Pract 2010; 10: 560-579.

13. Alexandre A, Corò L, Paradiso R, Treatment of symptomatic lumbar spinal degenerative pathologies by means of combined conservative biochemical treatments. Acta Neurochir Suppl 2011; 108: 127-135.

14. Bocci V, Zanardi I, Travagli V. Oxygen/ozone as a medical gas mixture. A critical evaluation of the various methods clarifies positive and negative aspects. Med Gas Res 2011; 1: 6.

15. Andreula CF, Simonetti L, De Santis F et al. Minimally invasive oxygen-ozone therapy for lumbar disk herniation. AJNR Am J Neuroradiol 2003; 24: 996-1000.

16. Steppan J, Meaders T, Muto M et al. A metaanalysis of the effectiveness and safety of ozone treatments for herniated lumbar discs. J Vasc Interv Radiol 2010; 21: 534-48.

17. Buric J, Molino Lova R. Ozone chemonucleolysis in non-contained lumbar disc herniations. A pilot study with 12 months follow-up. Acta Neurochir 2005; 92: 93-97.

18. Paradiso R, Alexandre A. The different outcomes of patients with disc herniation treated either by microdiscectomy, or by intradiscal ozone injection. Acta Neurochir 2005; 92: 139–142.

19. Muto M, Ambrosanio G, Guarnieri G et al. Low back pain and sciatica: treatment with intradiscal-intraforaminal O(2)-O (3) injection. Our experience. Radiol Med 2008; 113: 695-706.

20. Muto M, Andreula C, Leonardi M. Treatment of herniated lumbar disc by intradiscal and intraforaminal oxygen-ozone (O2-O3) injection. J Neuroradiol 2004; 31:183-9.

21. Oder B, Loewe M, Reisegger M et al. CT-guided ozone/steroid therapy for the treatment of degenerative spinal disease–effect of age, gender, disc pathology and multi-segmental changes. Neuroradiol 2008; 50: 777-85.

22. Gallucci M, Limbucci N, Zugaro L et al. Sciatica: treatment with intradiscal and intraforaminal injections of steroid and oxygen-ozone versus steroid only. Radiol 2007; 242: 907-13.

23. Gautam S, Rastogi V, Jain A et al. Comparative evaluation of oxygen-ozone therapy and combined use of oxygen-ozone therapy with percutaneous intradiscal radiofrequency thermocoagulation for the treatment of lumbar disc herniation. Pain Pract 2011; 11: 160-6.

24. Wu Z, Wei LX, Li J et al. Percutaneous treatment of non-contained lumbar disc herniation by injection of oxygen-ozone combined with collagenase. Eur J Radiol 2009; 72: 499-504.

25. Bonetti M, Fontana A, Cotticelli B et al. Intraforaminal O(2)-O(3) versus periradicular steroidal infiltrations in lower back pain: randomized controlled study. AJNR Am J Neuroradiol 2005; 26: 996-1000.

26. Paoloni M, Di Sante L, Cacchio A 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 2009; 34: 1337-44.

27. Gazzeri R, Galarza M, Neroni M et al. Fulminating septicemia secondary to oxygen-ozone therapy for lumbar disc herniation: case report. Spine 2007; 32: E121-3.

28. Bo W, Longyi C, Jian T et al. A pyogenic discitis at c3-c4 with associated ventral epidural abscess involving c1-c4 after intradiscal oxygen-ozone chemonucleolysis: a case report. Spine 2009; 34: E298-304.

29. Lo Giudice G, Valdi F, Gismondi M et al. Acute bilateral vitreo-retinal hemorrhages following oxygen-ozone therapy for lumbar disk herniation. Am J Ophthalmol 2004; 138: 175-7.

30. Corea F, Amici S, Murgia N et al. A case of vertebrobasilar stroke during oxygen-ozone therapy. J Stroke Cerebrovasc Dis 2004; 13: 259-61.

31. Ginanneschi F, Cervelli C, Milani P et al. Ventral and dorsal root injury after oxygen-ozone therapy for lumbar disk herniation. Surg Neurol 2006; 66: 619-20.

32. Devetag Chalaupka F, Caneve G, Mauri M et al. Thunderclap headache caused by minimally invasive medical procedures: description of 2 cases. Headache 2007; 47: 293-5.

Summary:

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Professor Campbell