Complementary Therapies in Medicine 59 (2021) 102724 Contents lists available at ScienceDirect Complementary Therapies in Medicine journal homepage: www.elsevier.com/locate/ctim Short Communication Ozone therapy versus surgery for lumbar disc herniation: A randomized double-blind controlled trial☆ Bernardino Clavo a, b, c, d, *, Francisco Robaina b, Gerard Urrutia e, Sara Bisshopp f, Yolanda Ramallo c, g, h, Adam Szolna f, Miguel A. Caramés b, María D. Fiuza a, Renata Linertová c, g, h a Research Unit, Dr. Negrín University Hospital, Las Palmas, Spain b Chronic Pain Unit, Dr. Negrín University Hospital, Las Palmas, Spain c Research Network on Health Services in Chronic Diseases (REDISSEC), Madrid, Spain d Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), BioPharm Group, Universidad de Las Palmas de Gran Canaria, Spain e Institut d’Investigació Biomèdica (IIB) Sant Pau - CIBERESP, Barcelona, Spain f Neurosurgery, Dr. Negrín University Hospital, Las Palmas, Spain g Canary Islands Health Research Institute Foundation (FIISC), Tenerife, Spain h Evaluation Unit of the Canary Islands Health Service (SESCS), Tenerife, Spain A R T I C L E I N F O A B S T R A C T Keywords: Objectives: Surgery is the treatment of choice for symptomatic disc herniation after conservative management. Cost-effectiveness Several studies have suggested the potential utility of intradiscal ozone infiltration in this pathology. The aim of Disc herniation this trial was to compare intradiscal ozone infiltration vs. oxygen infiltration vs. surgery. Microdiscectomy Design and interventions: This was a randomized, double-blinded, and controlled trial in patients on a waiting list Ozone therapy Randomized controlled trial for herniated disc surgery. There were three treatment groups: surgery; intradiscal ozone infiltration (plus foraminal infiltration of ozone, steroids, and anesthetic); intradiscal oxygen infiltration (plus foraminal infil­ tration of oxygen, steroids, and anesthetic). Main outcome measures: The requirements for surgery. Results: Five years after the treatment of the last recruited patient (median follow-up: 78 months), the require­ ment for further surgery was 20 % for patients in the ozone group and 60 % for patients in the oxygen group. 11 % of patients initially treated with surgery also required a second surgery. Compared to the surgery group, the ozone group showed: 1) significantly lower number of inpatient days: median 3 days (interquartile range: 3–3.5 days) vs. 0 days (interquartile range: 0–1.5 days), p = 0.012; 2) significantly lower costs: median EUR 3702 (interquartile range: EUR 3283–7630) vs. EUR 364 (interquartile range: EUR 364–2536), p = 0.029. Conclusions: Our truncated trial showed that intradiscal ozone infiltrations decreased the requirements for conventional surgery, resulting in decreased hospitalization durations and associated costs. These findings and their magnitude are of interest to patients and health services providers. Further validation is ongoing. 1. Introduction responsible for a huge medical and socio-economic cost, estimated in 2016 in United States at 134.5 billion US$.3 LBP, with or without sciatic According to the 2010 Global Burden of Disease Study, low back pain nerve involvement, affects approximately 70%–80% of the population at (LBP) is the sixth most common disease contributing to the global least once in their lifetimes,4 with a prevalence of 7.5 % in 2017.2 burden of disease, and significantly reduces quality of life.1 In 2017, The most common pathogenesis of LBP with nerve root compression globally, LBP remained as the most common musculoskeletal problem is lumbar disc herniation (LDH). After refractory conservative man­ and the most important cause of disability and absenteeism from work, agement, the treatment of choice for LDH is surgery (discectomy or with global years lived with disability of 64.9 million.2 LBP is also microdiscectomy), which is indicated in patients with intolerable pain, ☆ The authors obtained approval from the local Research Ethics Review Committee of Las Palmas (Spain) for this study and the above-mentioned clinical trials. * Corresponding author at: Research Unit, Chronic Pain Unit, Dr. Negrín University Hospital, 35019, Las Palmas, Canary Islands, Spain. E-mail address: bernardinoclavo@gmail.com (B. Clavo). https://doi.org/10.1016/j.ctim.2021.102724 Received 5 November 2020; Received in revised form 10 March 2021; Accepted 19 April 2021 Available online 5 May 2021 0965-2299/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). B. Clavo et al. Complementary Therapies in Medicine 59 (2021) 102724 Fig. 1. CONSORT flow diagram of the truncated study. progressive neurologic deficits or cauda equina syndrome.5 Nonetheless, the success rate of surgery tends to decrease on long-term follow-up due Table 1 to the onset of symptoms of failed back surgery syndrome, and addi­ Results summary and statistical analyses. tional conservative methods are required. Oxygen-ozone (O2O3) ther­ Surgery arm Ozone arm Oxygen arm Surgery vs. apy has been revealed to have a substantial pain relief effect and Ozone improve quality of life in patients affected by multifactorial LBP using Number of paravertebral infiltrations6–9 as well as in LDH using intradiscal patients infiltrations.10–17 Its application could be used to prevent or delay sur­ ITT 7 6 6 gery in patients who do not respond to conservative treatments. How­ PP 9 5 5 ever, to date, there are no randomized controlled trials (RCT) that Hospitalization compare O2O3 versus surgery. The aim of the current RCT was to days ITT 3 (3–3) 0 (0–3) 2.5 (0–6) P = 0.051 compare intradiscal O2O3 infiltration vs. oxygen (O2) infiltration vs. PP 3 (3–3.5) 0 (0–1.5) 2 (0–3.5) P = 0.012 surgery. Cost (EUR) ITT 3702 364 3729 P = 0.022 2. Material and methods (3336–6343) (364–3596) (364–5353) PP 3702 364 3552 P = 0.029 (3283–7630) (364–2536) (364–4035) This was a randomized, double-blinded (patients and outcomes Days from Infiltration arms assessor) parallel group study aimed to evaluate the effect of O2O3 enrolment to therapy in the management of patients with lumbar herniated disc treatment requiring surgery according to the criteria of our Department of ITT 81 (46–127) 15 (9–27) P = 0.005 PP 81 (51–144) 12 (8–25) P < 0.001 Neurosurgery. All patients provided informed written consent to participate in the trial, and all procedures conformed to the Declaration ITT: intention to treat analysis; PP: per protocol analysis. Surgery arm: dis­ of Helsinki of 1975. The clinical trial was approved by the Research cectomy or microdiscectomy. Ozone (O2O3) arm: O2O3 infiltration + ster­ Ethics Review Committee of Las Palmas (Spain) and, before the start of oids + anesthetic. Oxygen (O2) arm: O2 infiltration + steroids + anesthetic. After randomization, one patient from the O2O3 arm and another from the O2 the enrollment of patients, it was registered at http://www.clinicaltrials. arm requested surgery and were treated accordingly but without infiltration. gov (NCT00566007). Compared to discectomy and microdiscectomy, the shorter period from enroll­ The main objectives of this research were: 1) to evaluate the efficacy ment to treatment in the intradiscal infiltration groups was related to the easier of O2O3 infiltration versus O2 infiltration, 2) to evaluate the effective­ planning for the minimally invasive outpatient procedure compared with the ness of O2O3 infiltration versus surgery. The secondary objectives were: standard surgery approach. Values of P < 0.05 were considered statistically 1) to evaluate direct hospital costs, 2) to evaluate the safety of the significant. Differences between “O2 and O2O3” arms and “O2 and surgery” different procedures. arms were not statistically significant, and the p-values have not been presented There were three treatment arms: 1) surgery (standard treatment): in the Table 1. 2 B. Clavo et al. Complementary Therapies in Medicine 59 (2021) 102724 Fig. 2. Images pre- and post- ozone treatment. 59 years old patient on waiting list for surgery because a symptomatic, left paramedial L5-S1 disc herniation (red arrows), with small caudal migration, and S1compression. After random­ ized, blinded assignment, the patient was treated by intradiscal oxygen-ozone (O2O3) infiltration. Planned surgery was avoided. In the last magnetic resonance images (MRI), nine years after procedure, the patient remained without disc herniation relapse. Upper Left: Sagittal MRI pre-treatment. Upper Right: MRI three years post-treatment. Lower Left: Axial MRI pre-treatment. Lower Right: Axial MRI three years post-treatment. discectomy or microdiscectomy; 2) ozone (experimental): intradiscal using the exact Mann–Whitney U test (two-tailed). Values of P < 0.05 O2O3 infiltration (concentration: 27 μg/mL (μg O3/mL O2)) + foram­ were considered statistically significant. As a non-inferiority study, the inal infiltration of O2O3 + steroids + anesthetic; 3) O2 (sham control): per protocol analysis was considered more relevant; both per protocol intradiscal O2 infiltration + foraminal infiltration of “O2 + ster­ and by intention to treat analysis are described in Table 1. oids + anesthetic”. The neurosurgeons and follow-up physicians were blinded with respect to the infiltration arm. 3. Results The main inclusion criteria were the following: patients between 18 and 75 years of age; on waiting list for surgery following diagnosis of The median follow-up was 78 months (26–106). One of the five herniated disc; sciatic pain ≥ 5 on the visual analog scale (VAS); pain patients (20 %) initially treated with O2O3 infiltration required subse­ radiated to the appropriate area according to the herniated disc; on the quent surgery 10 months later. Three of the five patients initially treated waiting list for disc surgery. The main exclusion criteria were calcified or with O2 infiltration (60 %) required surgery at the 4th, 6th and 14th migrated herniated disc, herniated disc with indications for lam­ months, respectively. One out of the nine patients (11 %) initially inectomy or arthrodesis, clinically relevant partial paralysis, simulta­ treated with surgery required a second surgery eight months later, neous cervical and dorsal symptomatic herniated discs, and previous which was initially declined by the patient, but finally performed 33 lumbar spine surgery. months later. No adverse events related with infiltration procedure were Initially, the main variable was pain level assessment according to observed. Representative images are featured in Fig. 2. the VAS. The initial estimated sample size was 156 patients (52 per Compared to the surgery arm, patients treated with O2O3 in­ treatment arm). However, organizational issues beyond our control filtrations required fewer inpatient days: 3 (3–3.5) vs. 0 (0–1.5), P = obliged closure of the study, with only 19 patients having been enrolled 0.012 and had lower costs: EUR 3702 (EUR 3283–7630) vs. 364 between December 2008 and March 2014. Finally, the clinical outcomes (364–2536), P = 0.029. See details in Table 1. were requirements of surgery, safety, and days and costs of hospitali­ zation evaluated five years after treatment of the last recruited patient. 4. Discussion Fig. 1 shows the CONSORT diagram. Statistical analysis included inpatient days and costs from the first This report, for the first time in the literature, describes O2O3 treatment plus further surgery if required. Data from the treatment arms infiltration vs. O2 infiltration vs. surgery in patients with disc herniation are expressed as median (25th–75th percentiles) and were compared requiring discectomy or microdiscectomy. In our study, only 20 % of 3 B. Clavo et al. Complementary Therapies in Medicine 59 (2021) 102724 O2O3 infiltrated patients required further surgery, which is in agree­ the Instituto de Salud Carlos III (Spanish Ministry of Health and Social ment with the efficacy suggested by previous studies.10–14 This per­ Affairs, Madrid, Spain), which also supported this randomized clinical centage was clearly lower than the 60 % of O2 infiltrated patients trial (NCT00566007, EudraCT: 2007-007013-37). The publication of requiring further surgery. Our study agrees with a previous randomized, this manuscript and the ongoing confirmatory study (NCT03282695) is double-blind clinical trial describing the greater effect of O2O3 infil­ supported by a grant (PI 17/00120) from the Instituto de Salud Carlos III tration versus O2 infiltration by paravertebral approach.6 Our study also and by a grant (I19/18) from the Ilustre Colegio de Médicos de Las suggests that the addition of intradiscal O2O3 infiltration leads to better Palmas (Spain). clinical effect than the infiltration of corticosteroid and anesthetic alone, as previously described in another randomized double blind clinical Acknowledgments trial.14 However, whereas the two mentioned clinical trials6,14 showed results within 6 months of follow-up, our study shows a beneficial effect We would like to thank Dr. Victor Sierra, MD, and Dr. Arturo Gómez, for up to 5 years after follow-up, with the additional inclusion of a MD (Rehabilitation Department) for help in patient management, Mr. surgery group. Alfonso Landin (Accounting Department) for assessments of direct costs Compared to the surgery group, the O2O3 group required signifi­ of treatments and Mr Ramón Saavedra (Department of Medical Illus­ cantly lower number of inpatient days and had lower associated costs. tration) for help with MR images. The difference in treatment costs (around EUR 3000 per patient) agrees with the results in a large retrospective study (2589 patients) from References Cuba,18 and could be of additional interest for health services providers. On the other hand, the beneficial effect of O2O3 in pain has also been 1 Buchbinder R, Blyth FM, March LM, Brooks P, Woolf AD, Hoy DG. Placing the global burden of low back pain in context. Best Pract Res Clin Rheumatol. 2013;27(5): reported in knee osteoarthritis RCT19–21 as well as in different neuro­ 575–589. pathic pain syndromes in small studies, such as in trigeminal neural­ 2 Wu A, March L, Zheng X, et al. 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Final version review & approval. Yolanda Ramallo: Investigation; 17 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. Writing - review & editing; Final version review & approval. Adam 2008;113(5):695–706. Szolna: Investigation; Final version review & approval. Miguel A. 18 Borroto-Rodríguez V, Abreu-Casas D, Rodríguez de la Paz NJ, Prieto-Jiménez IL, Caramés: Investigation; Final version review & approval. María D. Álvarez-Rosell N. Economic study of the application of ozone therapy in the treatment of pain due to intervertebral disc herniation. Rev Chil Neurocirugía. 2019; Fiuza: Conceptualization; Formal analysis; Supervision; Validation; 45:113–121. Final version review & approval. Renata Linertová: Funding acquisi­ 19 Babaei-Ghazani A, Najarzadeh S, Mansoori K, et al. The effects of ultrasound-guided tion; Investigation; Writing - review & editing; Final version review & corticosteroid injection compared to oxygen-ozone (O2-O3) injection in patients with knee osteoarthritis: a randomized controlled trial. Clin Rheumatol. 2018;37(9): approval 2517–2527. 20 de Sire A, Stagno D, Minetto MA, Cisari C, Baricich A, Invernizzi M. Long-term effects Declaration of Competing Interest of intra-articular oxygen-ozone therapy versus hyaluronic acid in older people affected by knee osteoarthritis: a randomized single-blind extension study. J Back Musculoskelet Rehabil. 2020;33(3):347–354. The ozone therapy device Ozonosan alpha plus (Dr. Hänsler GmbH, 21 Lopes de Jesus CC, Dos Santos FC, de Jesus L, Monteiro I, Sant’Ana M, Iffezheim, Germany) was bought using a grant (PI EC 07/90024) from Trevisani VFM. Comparison between intra-articular ozone and placebo in the 4 B. Clavo et al. Complementary Therapies in Medicine 59 (2021) 102724 treatment of knee osteoarthritis: a randomized, double-blinded, placebo-controlled 24 Clavo B, Navarro M, Federico M, et al. Ozone therapy in refractory pelvic pain study. PLoS One. 2017;12(7), e0179185. syndromes secondary to cancer treatment: a new approach warranting exploration. 22 An JX, Liu H, Chen RW, et al. Computed tomography-guided percutaneous ozone J Palliat Med. 2021;24(1):97–102. injection of the Gasserian ganglion for the treatment of trigeminal neuralgia. J Pain 25 Clavo B, Navarro M, Federico M, et al. Long-Term Results with Adjuvant Ozone Res. 2018;11:255–263. Therapy in the Management of Chronic Pelvic Pain Secondary to Cancer Treatment. 23 Lin SY, Zhang SZ, An JX, et al. The effect of ultrasound-guided percutaneous ozone Pain Med.. 2021 https://doi.org/10.1093/pm/pnaa459. PMID: 33738491 (Online injection around cervical dorsal root ganglion in zoster-associated pain: a ahead of print). In press. retrospective study. J Pain Res. 2018;11:2179–2188. 5