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OZONIOTHERAPY AS PAIN TREATMENT IN LOWER LIMBS:
SYSTEMATIC REVIEW
Aline Vieira Nascimento Priesnitz1
Abstract: To evaluate through a systematic review the eectiveness of ozone therapy for the
treatment of pain in the lower limbs. Methods: To achieve this objective, the methodology adopted
involved a systematic search in the ScienceDirect, PubMed and SciELO databases, using a structured
combination of specic keywords. Literature review studies and clinical studies relevant to the theme
were included. The inclusion criteria involved the selection of studies in English, Portuguese and
Spanish that addressed the application of ozone therapy in the treatment of pain in the lower limbs.
We excluded articles that had no direct relationship with the theme, as well as case reports, case series,
coursework, theses and dissertations. Conclusion: Chronic pain in the lower limbs is a prevalent
condition, often caused by traumatic injuries, degenerative joint diseases, peripheral neuropathies
and/or circulatory disorders. In addition to the physical impact, this condition limits mobility and
signicantly aects people’s quality of life. Conventional treatments, although widely used, often
have limited ecacy and potential adverse side eects, driving the search for more eective and safe
therapeutic alternatives. Utilizing the oxidative potential of ozone, this therapy is administered in
various forms, including topical, subcutaneous, venous and rectal applications.
Keywords: Ozone therapy, oxygen-ozone therapy, acute pain, chronic lower limb pain.
INTRODUCTION
Chronic lower limb pain is a prevalent condition that aects individuals of all ages and
1 PhD student in Biomedical Sciences – Italian Institute of Rosario
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backgrounds. This pain can have dierent etiologies, including traumatic injuries, degenerative joint
diseases, peripheral neuropathies, circulatory disorders and even genetic factors (SUCUOGLU,
2021). Pain in the lower limbs not only causes physical discomfort, but can also signicantly limit
patients’ mobility and quality of life. Furthermore, it interferes with daily activities and contributes to
emotional suering, creating an urgent need for eective treatments to improve the condition of these
individuals (HASSANIEN, 2018).
The complexity of chronic pain demands a multidisciplinary therapeutic approach, various
treatments have been explored, from analgesics, opioids and anti-inammatory medications, to
physiotherapeutic and surgical interventions. However, many of these treatments have limited
eectiveness and can cause adverse side eects ( DRUMOND, 2000). Therefore, there is a constant
search for therapeutic alternatives that oer eective pain relief with an acceptable safety prole. In
this context, ozone therapy has emerged as a promising option due to its anti-inammatory, analgesic
and antioxidant properties (GARIN, 2008).
The challenges in treating chronic pain are multiple. Variability in patients’ response to
conventional treatments, the presence of comorbidities, and the chronic nature of pain complicate
eective management of this condition. Furthermore, many pharmacological treatments can cause
dependence or undesirable side eects, which limits their long-term use. Therefore, the need for
alternative treatments that can oer sustainable pain relief without signicant adverse eects is
evident (SMITH, 2017).
Ozone therapy is a treatment that uses the oxidative potential of ozone, a molecule composed
of three oxygen atoms. This therapy involves the administration of a gaseous mixture of oxygen and
ozone, which can be applied in a variety of ways, including topically, subcutaneously, intravenously
and rectally, depending on the condition. The conversion of medical oxygen into medical ozone ensures
that therapeutic ozone is obtained without by-products. This treatment has been widely studied and
applied to various health problems, due to its multiple benecial properties (GARIN, 2008).
The benets of ozone therapy are broad and include anti-inammatory, analgesic and
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antioxidant actions. Ozone can act as a powerful antiseptic, in addition to improving oxygen delivery
to tissues and releasing growth factors, promoting recovery in cases of vascular problems and
osteoarticular disorders (DRUMOND, 2000).
The application of ozone therapy in the treatment of chronic pain in the lower limbs is based
on its ability to modulate inammatory processes and improve tissue oxygenation. Preclinical and
clinical studies have shown that ozone can relieve pain and improve lower limb function, thanks
to its anti-inammatory and analgesic properties. These eects are achieved by local or systemic
administration of ozone, depending on the characteristics of the pain and the patient’s condition (
BOCCI, 2005).
Although ozone therapy has gained popularity as a therapeutic alternative, scientic evidence
on its eectiveness and safety in treating lower limb pain is still limited. The systematic review and
meta-analysis proposed in this work aim to gather and critically analyze the available studies on the
use of ozone therapy for the treatment of pain in the lower limbs (URITS, 2019 and DALL’OLIO,
2014).
Through this systematic review and meta-analysis, we seek to expand the understanding
of ozone therapy as a therapeutic option for pain management. Critically analyzing the available
literature, providing a solid basis for clinical decision making and advancing scientic knowledge in
this crucial area of clinical practice.
GOAL
To evaluate, through a systematic review, the eectiveness of ozone therapy for the treatment
of pain in the lower limbs, identifying the mechanisms of action of ozone therapy in relieving chronic
pain and comparing the results with other conventional treatments for chronic pain in the lower limbs.
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METHODOLOGY
The methodology of this literary review study involved carrying out systematic searches in
the PubMed and SciELO databases. To identify relevant and high-quality studies, a structured search
strategy was used by combining specic keywords. This approach included the selection of literature
review articles and clinical research relevant to the topic investigated. Articles that were not directly
related to the topic were excluded, as well as theses and duplicate articles between the databases, to
guarantee the relevance and exclusivity of the analyzed data. This procedure ensures that the review
covers only the most pertinent and rigorously evaluated evidence available in the scientic literature.
The following were adopted as inclusion criteria for searching for studies: studies that
evaluated dierent treatments for the correction of clinical treatment studies and exclusion criteria,
articles from any language other than English, Portuguese and Spanish were not used, articles unrelated
to the topic, in addition to reports and case series, course completion works, thesis and dissertations.
In the end, after applying the election criteria for the selection of literature, for the development of the
study, articles that do not t the pre-established criteria will be excluded and the selected articles of
greatest relevance on the topic will be used.
DATA COLLECTION PROCESS
For the work, research was carried out through scientic articles, where their contents were
extracted, such as authorship and year of publication, relevance of the present work and also the type
of study such as literature reviews and countries of origin. The evaluation of the data collected in
the review articles was carried out through a compilation of the main points relating to the following
aspects, using key words.
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DISCUSSION
Ozone therapy originated in Germany and the Soviet Union during the First World War,
and has since spread throughout Europe, China and America. However, only in Russia, Cuba, Spain
and Italy is this technique legal. The scientic literature on its use in pain is still limited. Studies
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demonstrate that ozone therapy has promising therapeutic potential ( CEDEÑO, 2020).
This technique is based on the application of a mixture of oxygen and ozone, used for
therapeutic purposes for many years. Recent studies indicate that the controlled application of ozone
can generate oxidative stress capable of correcting imbalances caused by acute or chronic oxidative
injuries. This treatment has been shown to increase the activity of antioxidant enzymes, neutralizing
the excessive formation of reactive oxygen species, promoting important therapeutic eects (WILSON,
GANDHI, SMITH, VATSIA, KHAN- 2017).
The analgesic eect of ozone on pain stands out as an eective therapeutic alternative, it is
often compared to the hyperbaric oxygen chamber (HBOT), however, the intra-articular application
of ozone is considered more eective, practical and economical. While HBO provides pure oxygen in
a pressurized environment, ozone therapy is a gaseous mixture of oxygen and ozone ( HERNÁNDEZ,
2012). And it triggers a series of mechanisms that normalize oxygen supply for several days, correcting
diseases associated with ischemia, infections and oxidative stress. ( VALLONE, 2014)
Ozone reacts with several biological compounds, promoting therapeutic benets. Its
mechanism of action is not yet fully understood, but it includes the inactivation of microorganisms,
the stimulation of oxygen metabolism and the activation of the immune system. Thus, ozone activates
cellular metabolism, reduces oxidative stress and increases tissue oxygen supply, providing pain relief
and improving joint function. ( MARQUEZ, 2011).
According to SEYAM et. al, (2018), this technique has been used as an alternative treatment
for knee osteoarthritis, aiming to improve patients’ symptoms and quality of life, since there is still
no cure for this pathology and the applications of ozone They can be performed periarticularly,
intraarticularly and subcutaneously, providing a diverse and minimally invasive approach to managing
pain and inammation associated with osteoarthritis.
According to ANZOLIN (2019), in the treatment of osteoarthritis, ozone acts as a
bioregulatory agent, releasing factors from endothelial cells and normalizing cellular redox status.
Furthermore, O3 inuences the levels of cytokines in the body, ozone reduces the concentration
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of TNF-α, a pro-inammatory cytokine that increases mitochondrial production of reactive oxygen
species (ROS) in osteoarthritis. By inhibiting TNF-α, O3 can interrupt the harmful NFkB pathway,
reducing inammation. Additionally, ozone increases levels of TGF-β1, a cytokine crucial for tissue
remodeling.
NFkB, although it is a fundamental regulator of inammatory responses and cell proliferation,
has eects that vary according to the type of cell and can promote cell proliferation or apoptosis. This
variability highlights the complexity of the inammatory response in osteoarthritis and the need for
treatments that can eectively modulate these responses. Thus, studies suggest that ozone therapy
may be a promising intervention to control inammation and improve the quality of life of patients
with knee osteoarthritis, although more research is needed to fully understand its mechanisms of
action and optimize its use (SEYAM et al ., 2018).
The benets of the technique using oxygen-ozone for treating pain in the lower limbs are
diverse. Ozone therapy has been shown to have analgesic properties, helping to reduce pain intensity
and signicantly improving patients’ quality of life, allowing them to resume their daily activities with
more comfort. Additionally, ozone has anti-inammatory eects, reducing inammation in lower limb
tissues, which is especially useful in conditions such as arthritis, where inammation contributes to
joint pain and stiness. Ozone therapy can also improve blood circulation, promoting wound healing,
reducing swelling and relieving the feeling of heaviness and fatigue in the legs. Another benet
is stimulation of the immune system, with ozone strengthening the immune system by increasing
the activity of white blood cells and promoting the release of growth factors that stimulate tissue
regeneration. It can be mentioned that it also has antimicrobial and antifungal properties, helping to
reduce the risk of secondary infections in wounds on the lower limbs. Furthermore, the pain relief
provided by ozone therapy can allow patients to reduce the amount of analgesic medications they take
regularly, thus minimizing the side eects associated with these medications. Many patients report a
rapid improvement in symptoms after treatment with ozone therapy, resulting in a faster recovery and
return to normal daily activities (ULUSOY, 2019).
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The main indications for ozone therapy for the lower limbs are varied. In cases of arthritis,
both osteoarthritis and rheumatoid arthritis can cause chronic pain and inammation in the joints
of the lower limbs. In this case, there is an indication to reduce joint inammation, relieve pain and
improve joint function in these patients. Muscle and joint injuries, such as muscle strains, ligament
sprains and joint injuries, can also be treated with ozone therapy, which accelerates healing, reduces
pain and restores normal function to the aected limb. In conditions of peripheral neuropathy, such
as diabetic neuropathy, nerve compression, and traumatic nerve injuries, ozone therapy improves
blood circulation around the nerves, reduces inammation, and relieves symptoms of neuropathy.
In circulatory disorders, such as chronic venous insuciency and peripheral arterial disease, ozone
therapy improves circulation, promotes ulcer healing and reduces associated pain. For patients with
chronic pain in the lower limbs, ozone therapy is an eective option for pain management, helping
to reduce pain intensity, improve physical function and increase quality of life (ANDRADE, 2019).
As an absolute contraindication, we have Glucose-6-Phosphate Dehydrogenase (G6PD)
deciency: Individuals with G6PD deciency may be at risk of hemolysis when exposed to ozone, due
to the increased production of free radicals. Therefore, ozone therapy is contraindicated in patients
with this condition (ULUSOY, 2019 and ANDRADE, 2019).
Among the limitations detected during the development of this systematic review, the small
number of published articles available that t the inclusion and exclusion criteria can be highlighted.
Although the selected studies had a good number of participants, none of them were carried out
considering specic cases and the Brazilian population.
CONCLUSION
Ozone therapy has demonstrated eectiveness in treating chronic pain in the lower limbs, as
evidenced by partial data from this ongoing study for a doctoral thesis. Preliminary results indicate
that ozone relieves pain, reduces joint stiness and improves physical capacity in patients with
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traumatic injuries, degenerative joint diseases and peripheral neuropathies. Its anti-inammatory and
analgesic properties, attributed to the antioxidant characteristics of ozone, are used through dierent
routes of administration, such as intra-articular and rectal, allowing personalized adaptation of the
treatment. Standardization of application protocols is essential to optimize clinical results, dening
ideal concentrations, frequency and duration of treatment. Considering the signicant prevalence
of pain in the lower limbs, the incorporation of ozone therapy as an accessible therapeutic option
in public health is relevant, oering safe and eective alternatives to improve patients’ quality of
life. However, more research is needed to conrm its long-term eectiveness and establish accurate
clinical guidelines. Continuing these investigations is essential to validate the full potential of ozone
therapy and its adequate implementation in clinical practice.
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