INTRODUCTION
The temporomandibular joint (TMJ), jaws, muscles, ligaments, periodontium, and dental organs constitute a harmonic functional stomatognathic unit. Any alteration on its components can result in homeostatic rupture known as TMJ disorders (TMD) with a set of signs and symptoms.[12] The American Dental Association includes TMD a heterogeneous group of clinical conditions that are characterized by pain and dysfunction of the masticatory system. The International Consortium Network established a model for pain research: the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). That tool was replaced in 2014 by the DC/TMD for both clinical and research use.
In an epidemiological study, with volunteers aged 18 to 44 years, it was found that every year 4% of the subjects developed a harmonic and functional stomatognathic system and the prevalence of painful TMD was high considering that 6 months later, 49% of incident cases exhibited TMD.[3] The most common TMD symptoms are articular crepitus, asymmetric mandibular movements, limited mouth opening, and facial muscle pain. This disorder can evolve to chronicity if proper treatment is not provided. TMD may negatively influence social and work relationships, and in consequence, decrease quality of life.[4]
TMD is frequent and even 1 of 10 patients with TMD suffers severe pain-related disability,[5] which directly affects their quality of life.[6] It has been reported that in TMD, there is an increased risk of presenting a greater number of painful sites as well as coexisting pain and comorbidities when the duration of pain in TMD is prolonged.[7] This persisting pain is probably attributable to the central sensitization mechanism, which is time-dependent. The disorder can evolve to chronicity if proper treatment is not provided. Hence, the importance of avoiding chronic pain, treating it in time with an effective therapy.[8] In that sense, the treatment of TMD is complex and requires a complete pharmacological scheme that includes anxiolytics, analgesics, muscle relaxants, and in some cases, even anti-depressants.[9] However, these treatments frequently have considerable adverse effects, making non-pharmacological and complementary approaches potentially advisable options for pain treatment.[10]
In daily clinical practice, the patients with TMD mainly request that the therapy helps to restore their masticatory capacity, as well as being able to chew without pain. Today, several potential intervention strategies have been tried as therapy for TDM,[11] however, an ideal strategy should be able to change harmful dynamics linked to prolonged disorders. Ozone gas was discovered in the 19th century. After years of research, this gas has been applied to the medical field, being an innovative treatment, which is known as ozone therapy (OT). The medical community has recently pointed out that OT could be helpful in the treatment of infectious diseases such as dental caries, to control blood cholesterol, to improve lumbar discectomy,[12] to augment immune and anti-oxidative responses, also in the complementary treatment of the hypoxic and ischemic syndromes.[13]
The practitioners must be choosing the best evidence-based medicine therapy and cost-effective for providing long-term pain relief for TDM. Therefore, we performed a comprehensive systematic review of clinical trials and observational studies to address the efficacy of OT in comparison with conventional treatment for pain relief (assessed using Visual Analog Scale (VAS)) and limited mouth opening (measured in mm) in patients with TDM.
DATA AND METHODS
Protocol registry
We conducted this systematic review according to the protocol registered in PROSPERO with the identification No. CRD42021242705 (Registration date: May 14, 2021).
Study design
The design of the studies included in the systematic review was randomized controlled trials, non-randomized clinical trials, cohorts and case-control studies. On the contrary, the studies excluded were case reports, case series, letters, comments, short communications, pilot studies, animal studies, in vitro studies, and literature reviews.
Eligibility criteria and participant characteristics of studies
The eligibility criteria were defined considering the PICO (Population, Intervention, Comparison, and Outcome) (Table 1).
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Table 1: Eligibility criteria according to PICO strategy and keywords used for the search
Search strategy and databases used
The algorithms used for the search strategy and the electronic databases used are shown in (Table 1). The search for grey literature was carried out on Scholar Google. The manual search was achieved through bibliographical references of the included studies in the review.
Study selection
The eligibility of the studies that could be included in the review was determined by reading the title and summary of each record identified at the search. Then the full-text of the selected articles that met the eligibility criteria were retrieved and reviewed in-depth. If reviewing the full-text, the studies that did not fully meet the eligibility criteria were excluded.
Data collection process and data items
A standardized Microsoft Excel worksheet was prepared for the registration of the relevant data of all included studies in the systematic review such as participant demographics and baseline characteristics; methodology; numbers of sessions and frequency; time intervals in which the effect of the intervention was measured; pain level score (the mean and standard deviation of Visual Analog Scale); maximal mouth opening (MMO); and Clinical Dysfunction Index at baseline and follow-ups. Two reviewers (MEMGC and EDTR) were responsible for data extraction, one reviewer extracted data, and the other revised the extracted data. The disagreements were discussed with all reviewers until reaching a consensus. The study researchers were contacted via email for missing data or additional details.
Risk of bias in individual studies and quality assessment
For assessment of the risk of bias of the included studies in the review, the recommendations from the Cochrane Handbook for Systematic Reviews of Interventions Chapter 814 and Risk of Bias 2 (RoB 2) tool were used for the assessment of the risk of bias.[15] Besides, we evaluated the quality of each study using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria.
Meta-analyses
The information collected from the selected studies was carefully analyzed to determine whether the studies can be grouped for each outcome (pain and MMO) and subgroups were performed using similar types of OT (transdermal and arthrocentesis) at the same time intervals of follow-up. Standardized mean difference was calculated for each study selected and then the data were combined using a random-effects meta-analysis. Besides, 95% confidence intervals and two-sided values were calculated. The heterogeneity among the studies, in terms of measures of effect, was evaluated using the I2 statistic. An I2 value greater than 50% was considered substantial heterogeneity.
RESULTS
After searching, it was found a total of 95 records. After removing duplicates, 74 records remained and these were revised by title and abstract. Then, 10 full-text articles were retrieved, 2 of which were excluded with reasons. Eight articles[1617181920212223] reported the use of OT for the treatment of TMD and the data extracted from these studies are listed in https://links.lww.com/MGAR/A73. No gray literature matched the eligibility criteria. The study selection process is detailed in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram (Figure 1). In the overall bias of the included studies, 25% exhibited some concerns and 75% had high risk; the main problems in the randomized controlled trials were reporting and selection bias. The risk of bias for individual studies is shown in Figure 2. Also, the certainty of the evidence was low due to risk of bias, inconsistency and imprecision as shown in (Table 2).
Figure 1: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of the selection process of the included studies in the systematic review.
Figure 2: Risk of bias of the included studies in the systematic review.Note: AOW: Arthrocentesis with ozonized water; ARL: arthrocentesis with Ringer lactate; ASS: arthrocentesis with saline solution; CDI: Clinical dysfunction index; OT: ozone therapy; PL: placebo; PT: pharmacological therapy; VAS: Visual Analog Scale.
Table 2: Quality assessment of the included studies
Ozone treatments
Four studies evaluated the efficacy of high-frequency, bio-oxidative transdermal OT in patients with TMD. The sessions lasted 10 minutes once, 6 times per 2 weeks. Doğan et al.[16] and Yamaner et al.[17] applied ozone at 30% of concentration. Differently, Celakil et al.[1819] performed two studies using an ozone concentration of 60%. On the other hand, three studies evaluated the efficacy of the ozone application in arthrocentesis of the TMJ with intraarticular disorder. The patients received 2 mL of ozonized water with 70 μg/mL.[202122] Finally, Daif[23] injected 2 mL of ozone gas concentration at 10 μg/mL into the articular fossa of the TMJ. The injections were repeated twice per week for 3 weeks.
Pain outcomes
Concerning transdermal OT, Doğan et al.[16] evaluated pain perception changes by VAS in patients with painful TMD. The control group with pharmacological therapy receives ketoprofen and thiocolchicoside twice a day for 7 days. Their team reported improvement of pain in favor of OT after 2 weeks of treatment. Also, Celakil et al.[18] evaluated subjective pain levels with VAS diagnosis of myofascial pain dysfunction syndrome. The control group received sham OT, in the same number of sessions with de ozone device switched on but not programmed. The research team reported improvement in pain after 2 weeks of OT treatment. Two years later, Celakil et al.[19] evaluated OT versus occlusal splint (OS) worn every night for 4 weeks. The team reported improvement of pain in both groups. Finally, Yamaner et al.[17] assessed OT versus sham OT. The team reported improvement of pain in the intervention group after one month of treatment.
On the other hand, there was evidence of the OT used in temporomandibular joint arthrocentesis. Hammuda et al.[20] and Elsholkamy[22] assessed pain with VAS in the TMJ with intraarticular disorder. The control group receives arthrocentesis with 2 mL of saline solution. Both studies reported improvement of pain with OT after 1 year. Also, Shabaan and Sabry[21] assessed VAS in TDM patients with anterior disc displacement without reduction. The control group receives arthrocentesis with 2 mL of Ringer lactate. Also, 875 mg of amoxicillin and 125 mg of clavulanic acid twice a day for 5 days and diclofenac potassium 50 mg three times daily were administered in both groups. The team reported improvement of pain using OT after one year.
Maximal mouth opening
Related to transdermal OT, Doğan et al.[16] reported no significant differences between therapies. On the other hand, Celakil et al.[18] reported an improvement in MMO after 2 weeks of OT treatment in comparison to sham OT. However, 2 years later, Celakil et al.[19] reported no significant differences between OT and occlusal splint. Finally, Yamaner et al.[17] reported no significant differences between treatments. On the other hand, concerning arthrocentesis with ozone, another three studies[202122] reported an improvement in MMO in TMD treated with OT.
Clinical dysfunction outcomes
Only one study assessing clinical dysfunction index met inclusion criteria, Daif[23] evaluated the index of Helkimo in patients with bilateral internal derangement of the TMJ and disc displacement with reduction. The intervention group treated with OT was injected by 2 mL of ozone gas at 10 μg/mL of concentration into the articular fossa of the TMJ; the control group treated with pharmacological therapy received ibuprofen and chlorzoxazone three times per day for 2 weeks. The team reported improvement of clinical disfunction index in favor of OT after 2 weeks of treatment.
Meta-analyses
The results of the meta-analyses are shown in Figure 3.
Figure 3: Meta-analyses of the efficacy of OT for pain (assessed by visual analog scale; A) and maximal mouth opening (B). Meta-analyses of the efficacy of OT for pain (assessed by visual analog scale; A) and maximal mouth opening (B).Note: OT: Ozone therapy.
DISCUSSION
The purpose of this review is to determine the efficacy of OT for the treatment of TMD. We included 8 studies with 234 participants suffering limited function and pain related to TMD. The plausible applicability of OT in the clinical practice of dentistry has been postulated due to the anti-hypoxic, anti-microbial, anti-inflammatory, and analgesic properties of the ozone.[24] This molecule has been tested to treat early carious lesions, tooth sensitivity, fissure lesions, dental plaque, periodontal pockets, ulcerations, herpetic lesions, and peri-implantitis. Additionally, ozone can be used as a cleaner of removable dentures and decontamination of dental instruments.[25]
OT can reduce pain because ozone increases the synthesis of superoxide dismutase, malondialdehyde, catalase, and the local release of catecholamines.[26] Besides, interleukin-6 and tumor necrosis factor-α levels in the synovial liquid of the TMJ are reduced.[27] This represents an increase in the threshold and a reduction in the responsiveness at the peripheral sensory nerve fibers.[28] This mechanism explains the results of the included studies that OT can diminish pain in TMD. Unfortunately, these clinical studies exhibited great heterogeneity, high risk of bias and low quality. Besides, two trials of transdermal OT[1718] had only a placebo as a control group. This approach of comparing the effect of an intervention with placebo (untreated control group) leads to overestimations of the treatment effects, so the control group should be treated with a standard treatment rather than nothing.[29] This could explain the heterogeneity of the effect of the intervention found across the studies included in the meta-analysis. On the other hand, two studies had the best available therapy (occlusal splint[18] or pharmacological therapy[30]) as a control group, which could provide information about potential side effects.[31] Unfortunately, the follow-up in the included studies was heterogeneous and short (1 week[16] or 1 month[19]), and none of the studies aimed to report side effects. Similar issues were found in the studies related to arthrocentesis with ozonized water.
On the other hand, OT can improve angiogenesis and wound healing, which is exemplified by the fact that ozone accelerates cell cycle and increases the release of interferons and interleukins.[32] In addition, ozone can induce the synthesis of transforming growth factor β that is a regulator for inflammatory responses and the entire wound healing.[33] Therefore, the improvement in wound healing outcomes may be related to the recovery of function in TMD. However, the evidence points out that OT fails to improve MMO, due to the included studies showing heterogeneous results between them. Besides, only one study evaluated the clinical index but showed high risk of bias and low quality.
Nowadays, the dose, concentration, times, frequency, and recommendations for OT are still without consolidation. Therefore, more high-quality research with a low risk of bias to consolidate the knowledge concerning OT in dentistry is required.
OT can diminish pain and improve the MMO in TMD, particularly when OT is used in arthrocentesis. However, there is no conclusive evidence that OT acts as a superior treatment for TMD compared with occlusal splint and pharmacological therapy. The studies reviewed a broad range of comparators, application methods, ozone concentration, treatment sessions, and follow-up. Conclusions cannot be drawn due to the heterogeneity in the methodology applied, the small number of current investigations, and the few research teams in the field. Therefore, there is the need for more research with double-blind clinical trials that should be performed to consolidate the knowledge in the area before considering the use of OT in the treatment of TMD in clinical practice.
Author contributions
RTR and LAF conceived the review; RTR, MEMCG, LAFM, EUTR, RMNG and LAF collected and analyzed the data; and RTR and AFL led the writing. All authors approved the final manuscript.
Conflicts of interest
All authors confirm that there no conflicts of interest that could inappropriately influence this work.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Additional file
Additional Table 1: Characteristics and results of the included studies in the systematic review.
Acknowledgements
RTR and LAF thanks to CA-63 “Cuerpo académico Investigación en Salud”; LAF thanks to Investigadoras e Investigadores por México CONACyT program.
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