Abstract
We reply to the commentary by Franzini et al. regarding our double-blind randomized controlled trial comparing ozone-oxygen injection against pure oxygen for chronic discogenic low back pain. While we welcome scientific discourse, the commentary mischaracterizes key aspects of our methodology and findings. We assert that the use of pure oxygen was a critical innovation designed to isolate the therapeutic effect of ozone from its carrier, addressing a major gap in the literature. Furthermore, we reiterate that our observed clinical improvements (ΔVAS = 5.6) are well above established thresholds for clinical significance. We also clarify that the commentary's extensive theoretical risk model is somewhat disconnected from our empirical safety data (no major adverse events) and the standard practices of mechanistic discussion. We conclude that critique must be data-driven and proportionate to the study's stated aims, and that our trial provides promising data advancing the field of interventional ozone therapy.
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Introduction
We appreciate the thoughtful engagement of Franzini et al. with our recent publication examining ozone-oxygen versus pure oxygen injections for chronic discogenic low back pain. Constructive dialogue is essential for refining methodology and advancing clinical practice. However, several points raised in their commentary appear to misrepresent the purpose, methods, and interpretation of our trial. We address these here to ensure clarity for readers and the scientific community.
Study aim and design
Our study was designed to investigate whether the clinical effects of paravertebral ozone therapy arise specifically from ozone rather than from its oxygen carrier. To our knowledge, this was the first double-blind randomized controlled trial to compare ozone-oxygen directly with pure oxygen. This design was intentional: isolating ozone's therapeutic role is a necessary step toward understanding mechanism and optimizing practice. Far from a limitation, the use of pure oxygen as the control was the pivotal methodological innovation of our trial.
On the use of pure oxygen as control
The commentary suggests that pure oxygen is an inadequate comparator. In contrast, we selected it precisely for its scientific relevance. Oxygen is the carrier used in all ozone preparations; therefore, comparing ozone-oxygen against oxygen alone provides the correct mechanistic control. Previous trials compared ozone with steroids or other therapies—none distinguished ozone's independent effect. Our approach adds clarity to this literature rather than weakening it.
Clinical outcomes and interpretation
Franzini et al. questioned the clinical significance of the observed improvement in pain scores (ΔVAS = 5.6). Generally, a change greater than 2 points on the VAS or 30% improvement represents a clinically meaningful benefit in pain research. Our results substantially exceeded these thresholds, and parallel ODI improvements reinforce this as a genuine functional gain. These outcomes warrant recognition, even within the constraints of a pilot trial.
Methodological considerations
Concerns about injection volume, dose precision, and anatomical variation were addressed transparently in our methodology. The volume and dosage followed published standards, and ultrasound guidance minimizes anatomical variability through direct real-time imaging. Under such control, variation in target accuracy is negligible and does not represent a critical bias.
Safety and the “theoretical risk model”
A major part of the commentary develops a theoretical hazard model unrelated to our reported data. While we share the commitment to procedural safety, this mathematical exercise is speculative and disconnected from the empirical outcomes. Our trial observed no major adverse events, consistent with previous clinical literature. Theoretical modeling is valuable for hypothesis generation but cannot substitute for actual trial evidence when evaluating safety.
Blinding procedures
It was suggested that blinding might have been compromised due to ozone's odor. We implemented a rigorous double-blind protocol: an independent operator prepared gases using coded assignments, identical equipment, and identical injection procedures. No reports of suspected unblinding occurred. Verification by participant guessing, while a good refinement for future studies, does not invalidate the integrity of our current blinding strategy.
Mechanistic discussion
Our discussion referenced recognized biochemical pathways, such as modulation of oxidative stress and anti-inflammatory mediators, drawn from prior research. Commenting that these are “speculative” overlooks their acknowledged role in contextualizing results. Clinical discussions routinely explore plausible mechanisms based on existing evidence; our statements were fully in line with standard scientific practice.
Limitations and future directions
We clearly stated the pilot nature of our study—limited sample size and 3-month follow-up—as constraints warranting cautious interpretation. These limitations were openly acknowledged and will be addressed in ongoing trials with expanded cohorts and extended observation periods. We welcome constructive guidance grounded in these methodological realities rather than speculative extensions beyond the study's scope.
Conclusion
We express our gratitude to Franzini et al. for their involvement and emphasize our mutual objective of promoting evidence-based comprehension of ozone therapy for spinal pain. Empirically based critiques are essential for scientific advancement, especially in emerging interventional fields. We hope that future discussion will focus on data-driven evaluation and interactive improvement of methodology rather than speculative modeling. Our findings underscore ozone therapy's promising clinical profile and encourage further controlled studies to confirm and further validate these results.
Footnotes
Ethical approval
As per the original publication.
Informed consent
As per the original publication.
Author contributions
Both authors participated in writing this reply commentary.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
As per the original publication.