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Background Results from several randomized controlled trials have shown a beneficial effect of ozone in reducing postsurgical complications after impacted mandibular third-molar surgery, but the literature is lacking a systematic review and meta-analysis. Methods The authors conducted this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines after exclusion and inclusion criteria were applied and the following outcome parameters were evaluated: pain, swelling, trismus, quality of life, number of analgesics consumed, and adverse events. RevMan Cochrane Collaboration software, Version 5.3, was used to perform meta-analysis and the Grading of Recommendation Assessment, Development and Evaluation approach was used to rate the certainty of evidence. Results Patients who underwent adjuvant ozone application reported lower pain scores than patients in the control group at 24 hours after surgery (95% CI, –3.94 to –1.56) and at 7 days (95% CI, –1.67 to –0.78). Pooled analysis of all 4 included trials revealed a standardized mean difference (SMD) in swelling of –0.44 at 24 hours, 0.63 at 72 hours, and –0.87 at 7 days after surgery in the experimental group. Higher mean estimates in mouth opening were experienced by patients who received ozone at 24 hours (SMD, 2.74; 95% CI, –1.93 to 7.41; 4 studies, 133 patients), 72 hours (SMD, 2.77; 95% CI, –0.63 to 6.17; 4 studies, 133 patients), and 7 days after surgery (SMD, 1.42 SMD; 95% CI, –1.34 to 4.18; 4 studies, 133 patients). Practical Implications Evidence suggests that adjuvant ozone application can offer some benefit for reducing pain, improving quality of life, and decreasing mean intake of analgesics after impacted mandibular third-molar surgery, but it is not effective in reducing facial swelling and trismus, which paves the way for future research.
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Systematic Review
Efcacy of adjuvant ozone therapy in
reducing postsurgical complications following
impacted mandibular third-molar surgery
A systematic review and meta-analysis
Kirti Chaudhry, MDS; Neeti Rustagi, MD; Rishi Bali, MDS; Shruti Khatana, MDS;
Shailendra Kumar, BDS; Amanjot Kaur, MDS; Pravin Kumar, MDS
ABSTRACT
Background. Results from several randomized controlled trials have shown a benecial effect of
ozone in reducing postsurgical complications after impacted mandibular third-molar surgery, but the
literature is lacking a systematic review and meta-analysis.
Methods. The authors conducted this systematic review according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses guidelines after exclusion and inclusion criteria
were applied and the following outcome parameters were evaluated: pain, swelling, trismus, quality
of life, number of analgesics consumed, and adverse events. RevMan Cochrane Collaboration
software, Version 5.3, was used to perform meta-analysis and the Grading of Recommendation
Assessment, Development and Evaluation approach was used to rate the certainty of evidence.
Results. Patients who underwent adjuvant ozone application reported lower pain scores than
patients in the control group at 24 hours after surgery (95% CI, e3.94 to e1.56) and at 7 days (95%
CI, e1.67 to e0.78). Pooled analysis of all 4 included trials revealed a standardized mean difference
(SMD) in swelling of e0.44 at 24 hours, 0.63 at 72 hours, and e0.87 at 7 days after surgery in the
experimental group. Higher mean estimates in mouth opening were experienced by patients who
received ozone at 24 hours (SMD, 2.74; 95% CI, e1.93 to 7.41; 4 studies, 133 patients), 72 hours
(SMD, 2.77; 95% CI, e0.63 to 6.17; 4 studies, 133 patients), and 7 days after surgery (SMD, 1.42
SMD; 95% CI, e1.34 to 4.18; 4 studies, 133 patients).
Practical Implications. Evidence suggests that adjuvant ozone application can offer some benet
for reducing pain, improving quality of life, and decreasing mean intake of analgesics after impacted
mandibular third-molar surgery, but it is not effective in reducing facial swelling and trismus, which
paves the way for future research.
Key Words. Impacted mandibular third molar; systematic review; ozone; pain; swelling; trismus.
JADA 2021:152(10):842-854
https://doi.org/10.1016/j.adaj.2021.05.006
Removal of impacted mandibular third molars (IMTM) is one of the most common surgical
procedures performed in dental clinics and is associated with postsurgical complications
(PSCs), such as pain, swelling, and trismus.
1
PSCs can have a negative impact on patients
quality of life due to increased workplace absence, follow-up appointments, expenses, and prolonged
medication use to address them.
2,3
Various pharmacologic and nonpharmacologic techniques have been developed to manage
PSCs.
4,5
The use of local or systemic corticosteroids and nonsteroidal anti-inammatory drugs is
often recommended to reduce pain, swelling, and trismus.
6-8
However, their limited success and
associated adverse effects have led clinicians to search for nonpharmacologic adjunctive therapies,
for example, low-level laser therapy, ozone therapy, cryotherapy, pulsed electromagnetic energy
therapy, and acupuncture.
9,10
Ozone has a positive effect on the metabolism of various cellular components in tissue, promotes
hemostasis, inhibits bacterial growth, and increases supply of oxygen to local surgical sites.
11,12
It has
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842 JADA 152(10) nhttp://jada.ada.org nOctober 2021
been shown to have benecial effects on the healing and prevention of alveolar osteitis.
13
Results
from numerous randomized controlled trials (RCTs) have suggested a positive effect of ozone as an
adjunctive therapy in reducing PSCs, but consensus is still lacking.
14-17
The aim of our systematic review and meta-analysis was to compare the efcacy of ozone therapy
with a placebo or control in reducing PSCs associated with the surgical extraction of IMTMs.
METHODS
We performed this review in accordance to the latest Preferred Reporting Items for Systematic
Reviews and Meta-Analyses statement,
18
and the ow diagram is shown in Figure 1.
Literature search
Two authors independently searched MEDLINE, Cochrane, and Google Scholar using the key
words mandibular,third molar,extraction,impaction,removal,wisdom tooth,adjunctive therapy,and
ozone (Appendix; available online at the end of this article). We also searched for the registered
trials on trial registries and online databases of oral and maxillofacial surgery journals. The gray
literature was searched by means of reviewing the rst 100 hits on Google Scholar. This literature
search was performed from February 1 through February 28, 2020, and was updated in May 2020.
The references of relevant articles were also examined to identify eligible studies.
Eligibility criteria
RCTs and quasi-RCTs comparing the efcacy of adjuvant ozone therapy with a placebo for reducing
the severity of PSCs after IMTM surgical extraction with a minimum follow-up of 72 hours with
standardized outcomes were included. The intervention of interest was application of any regimen
of ozone after IMTM surgical extraction because there is no standardized ozone therapy regimen.
Trials reporting the results of any of the outcomes (that is, pain, swelling, trismus, and adverse
effects) of interest were included. We placed no restrictions on patient characteristics, molar
impaction types, types of ozone regimen used, or the methods used to measure the outcomes of
interest.
Study selection and data extraction
Two reviewers (S. Khatana, S. Kumar) worked independently and screened the titles and abstracts
of identied studies for possible inclusion in the study and then screened full texts for potential
eligibility. Any disagreement was resolved by means of discussion with the third author (R.B.). The
other 2 reviewers (A.K, K.C.) extracted data from the included studies independently using the
standard data collection form 2013 08 12 of the Cochrane Collaboration.
19
If any study had more
than 1 intervention arm, then only the ozone intervention arm was included.
Reviewers abstracted the characteristics of included studies, depicting the study and population
characteristics, outcomes assessed (ozone application methods, pre- and postoperative
cointerventions, pain, swelling, trismus, quality of life, additional analgesic use, adverse effects), and
their timelines. Outcomes reported at 24 hours, 72 hours, and 7 days postoperatively were selected
for analysis.
Summary measures and data synthesis
For the outcome of pain, the mean of patient-reported postoperative pain scores in the intervention
and control group was used. Pain was measured in all 4 trials included
14-17
using a visual analog
scale. All of the authors used vernier calipers to measure interincisal mouth opening.
14-17
For
trismus outcomes, the mean change from baseline was assessed in the intervention and control
groups.
The investigators measured swelling from different landmarks on the face instead of a single
measurement and means and standard deviations were pooled to obtain a single swelling mea-
surement. Variability was observed across trials in the methods and devices used to measure the
swelling, and investigators used different statistics to report it. For assessing swelling, we used the
standardized mean difference (SMD) and its 95% CI to pool the results. For studies in which
the authors did not report data in a way that allowed pooling in meta-analysis, the results were
summarized narratively.
ABBREVIATION KEY
GRADE: Grading of
Recommendations
Assessment,
Development and
Evaluation.
IMTM: Impacted
mandibular third
molar.
NA: Not applicable.
PSC: Postsurgical
complication.
RCT: Randomized
controlled trial.
JADA 152(10) nhttp://jada.ada.org nOctober 2021 843
Data analysis
RevMan Cochrane Collaboration software (Version 5.3) was used to perform meta-analysis, and the
results were displayed via forest plots. Statistical signicance was considered as P<.05. Statistical
heterogeneity was dened as P<.1 and I
2
>50%. The generic inverse variance method was chosen
a priori to pool the results using random-effects model because of clinical variability in the inter-
vention and trial designs to calculate the mean estimate of effects of ozone at 3 times for each
outcome of interest. Publication bias was not assessed quantitatively owing to the small number of
studies.
Sensitivity and subgroup analysis
Sensitivity analysis was done assuming no correlation between intervention and control arms in
split-mouth arms. This assumption that split-mouth trials and parallel trials are the samedwhich
provides the most conservative estimate of treatment effectdwas also adopted by Dawdy and
colleagues.
20
No subgroup analysis was done for the pooled outcomes.
Assessing risk of bias of included studies
Two reviewers (K.C., N.R.) assessed risk of bias of the included studies independently using the
Cochrane Handbook for Systematic Reviews of Interventions for guidance.
21
The risk of bias was
designated as high or low in the following areas: random sequence generation, allocation
concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete
outcome data, selective outcome reporting, and other bias. The third reviewer (R.B.) resolved any
disagreement.
Records excluded
(on the basis of title n = 144, on
the basis of abstract n = 5)
Full-text articles excluded,
with reasons
(n = 0)
Records after duplicates removed
(n = 153)
Records screened
(n = 153)
Full-text articles assessed
for eligibility
(n = 4)
Studies included in
qualitative synthesis
(n = 4)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 4)
IdenticationScreeningEligibilityIncluded
No. of records identied through database
searching (MEDLINE = 143; Clinical Trials
Registry-India = 0; Google Scholar = 4;
Cochrane = 12; American Trial Register = 0;
World Health Organization International Clinical
Trials Registry = 0; Medical Research Council = 0;
National Health Service Trial Registers = 0)
Additional records identied through other
sources (online databases of oral and maxillofacial
surgery journals) (International Journal of Oral
and Maxillofacial Surgery = 2; Journal of Oral and
Maxillofacial Surgery = 7; Journal of
Cranio-Maxillofacial Surgery = 0; British Journal of
Oral and Maxillofacial Surgery = 0; Journal of
Maxillofacial Oral Surgery = 0)
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses ow chart.
18
844 JADA 152(10) nhttp://jada.ada.org nOctober 2021
Dealing with missing data
All included trials were assessed for missing data, and the authors of relevant studies were contacted
to request access to the missing data. In instances for which there were randomly missing data, we
used the reported data.
Certainty of the evidence assessment
We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE)
approach (eTable, available online at the end of this article) to assess the certainty of the estimates
of effect for each outcome.
22
Evidence Prime software (GRADEPro) was used to summarize key
information for all outcomes.
The potential limitations to ascertain the quality of evidence were considered in light of risk of
bias, inconsistency, imprecision, indirectness of evidence, and publication bias.
23-26
Imprecision was examined using the clinical thresholds that aimed to ascertain the magnitude of
effects considered as clinically relevant for each outcome. We determined similar thresholds for
outcomes assessed, as discussed by Dawdy and colleagues.
20
In the maxillofacial eld, the minimal
clinically important difference
27
has not been determined for pain, swelling, or trismus.
RESULTS
Description of the included studies
The data extracted from the included studies
14-17
are summarized in Tables 1 through 3. A total of
133 records were screened and 4 RCTs published between 2013 and 2020 met the eligibility
criteria.
14-17
Three studies
15-17
had a split-mouth design (with crossover window being 2, 3, and 4
weeks, respectively), and 1 study had a parallel design.
14
Kazancioglu and colleagues
14,15
conducted
1 split-mouth design study and 1 parallel trial. Both studies followed similar protocol for experi-
mental and comparison groups and cointerventions administered. Variability was observed between
the other 2 included studies
16,17
for protocol followed for experimental group and the control group
and cointerventions administered by investigators to both group of participants (Table 2).
Variable modes of ozone application were used in the studies identied for detailed review. Two
studies used an extraoral ozone probe,
14,15
another used ozonated water irrigation,
17
and another
used topical ozone gel application.
16
Because no standard application for ozone is recommended in
the literature, all modes of ozone application were included in this review.
Characteristics of patients included
All 4 trials included patients with IMTMs with similar surgical difculty index according to Pell and
Gregory classication.
14-17
The operative time was reportedly lower in Glória and colleagues
17
(15
minutes) for both experimental and control groups. Kazancioglu and colleagues
14,15
reported it was
approximately 22 minutes for the experimental group and 25 minutes for the control group in both
studies, and Sivalingam and colleagues
16
reported longer surgery time for the experimental group
(mean [standard deviation], 22 [14] minutes) than the control group (mean [standard deviation], 20
[12] minutes). In all of the studies, age and sex distribution, IMTM difculty index, and mean
surgical time were comparable in both arms, indicating that patient factors had minimum con-
founding effect on the outcomes assessed.
Risk of bias
A tool from the Cochrane Collaboration
21
was used to assess the risk of bias of each study, as shown
in Figure 2. Low-quality reporting of methodological details inuenced the risk-of-bias assessment.
The domains that lacked sufcient information to suggest that authors took precautionary measures
to reduce biases were judged as being high risk. High risk of selection bias was considered if unclear
or no descriptions of the methods were provided regarding random sequence generation and allo-
cation concealment of participants in the included trials. Lower risk of bias was observed for do-
mains regarding blinding of participants and personnel and blinding of outcomes assessment.
The studies in which participants were not blinded to the intervention through use of pseudo-
ozone generator
14
or topical application,
16
the subjective outcomes assessment (that is, pain and
quality of life) could have been affected because participants might have been aware of receiving the
ozone intervention. Low risk of attrition bias was observed among the trials due to the short-term
JADA 152(10) nhttp://jada.ada.org nOctober 2021 845
nature of the procedure and need for postoperative follow-up of included participants. The selective
outcome reporting bias was ascertained to be low as in all the included trials, investigators reported
the outcomes data with dispersion, which could be pooled for meta-analysis. Except for Glória and
colleagues,
17
who published their protocol in a US trial registry (ClinicalTrials.gov), none of the
study protocols were available in the public domain.
Effects of ozone
The meta-analysis was done for all outcomes at 24 hours, 72 hours, and 7 days after surgery. Tables 1
through 3 present summaries of the studies included, and nal effect estimate and GRADE certainty
of evidence ratings for each outcome at each time are provided in the eTable (available online at
the end of this article).
Effects of Ozone on Pain
Investigators with all 4 trials
14-17
reported pain at 24 hours, 72 hours, and 7 days after surgery, with
the exception of Glória and colleagues,
17
who did not report nding at 7 days (Figure 3). Patients
who underwent adjuvant ozone application reported lower pain scores than patients in the control
group at 24 hours after surgery (e2.75 points on a 10-point scale in which 0 represents no pain and
10 represents unbearable pain), 95% CI, e3.94 to e1.56 points; 4 studies, 133 patients), at 72 hours
after surgery (e2.93 points; 95% CI, e3.77 to e2.08 points; 4 studies, 133 patients), and 7 days
after surgery (e1.22 points; 95% CI, e1.67 to e0.78 points; 3 studies, 113 patients) (Figure 3).
Sensitivity analysis revealed that the mean difference (MD) in pain scores between the ozone and
control arms was higher among patients recruited in the parallel trial than those recruited in the
split-mouth trial at 24 hours and 72 hours, but not after 7 days.
Effects of Ozone on Swelling
All 4 trials
14-17
were included to calculate mean estimate of swelling at all 3 times studied. Figure 4
shows that pooled analysis of all 4 trials revealed the SMD in swelling was e0.44 (95% CI, e2.61 to
Table 1. Characteristics of the included studies.
14-17
PARTCIPANTS, NO.
SURGERY TIME, MIN, MEAN
(STANDARD DEVIATION)
STUDY DESIGN
POPULATION
CHARACTERISTICS
AGE, Y, MEAN
(STANDARD
DEVIATION),
RANGE
MALE/
FEMALE,
NO. Intervention Comparison Intervention Comparison
Kazancioglu and
Colleagues,
14
2014
RCT*
Parallel, 3 arms
Group 1: 20
patients, low-level
laser therapy
Group 2: 20
patients, ozone
Group 3: 20
control patients
Impacted IIIb
surgical difculty
grade
22.6 (2.3),
18-25
32/28 20 20 22 (9) for
ozonated
25 (11) for
control
23 (8) for low-
level laser
terapy
excluded
Kazancioglu and
Colleagues,
15
2014
RCT
Split-mouth,
crossover window
period of 2 wk
Impacted IIIb
surgical difculty
grade
22.6 (2.3),
18-25
32/28 60 60 22 (9) for
ozonated
25 (11) for
control
Sivalingam
and
Colleagues,
16
2016
RCT
Split-mouth,
crossover
window period
of 3 wk
Similar difculty
index as assessed by
grading system
25.6 (4.4) 17/16 33 33 22 (14) for
ozonated
20 (12) for
control
Glória and
Colleagues,
17
2020
RCT
Split-mouth,
crossover
window period
of 4 wk
Bilateral impacted
third molar with
class II position, type
B impaction
20.9 (Not
available)
8/12 20 20 15.65 (6.94) for
ozonated
15.90 (5.56)
for control
* RCT: Randomized controlled trial.
846 JADA 152(10) nhttp://jada.ada.org nOctober 2021
1.73; 4 studies, 133 patients) at 24 hours after surgery; 0.63 (95% CI, e1.42 to 2.69; 4 studies, 133
patients) at 72 hours after surgery; and e0.87 (95% CI, e2.31 to 0.56; 4 studies, 133 patients) at 7
days after surgery in the experimental group.
Sensitivity analysis revealed that the SMD in swelling between both arms was lower among
patients recruited in split-mouth trials than in those recruited in parallel trials at 24 hours, 72 hours,
and 7 days, but none of these were statistically signicant (Figure 4).
Effects of Ozone on Mouth Opening or Trismus
All 4 trials
14-17
were included in the meta-analysis to study the effect of adjuvant ozone on trismus
compared with patients in the control arm for all 3 times studied (Figure 5). Higher mean estimates
were experienced by patients who received ozone at 24 hours after surgery (SMD, 2.74; 95% CI,
e1.93 to 7.41; 4 studies, 133 patients), 72 hours after surgery (SMD, 2.77; 95% CI, e0.63 to 6.17; 4
studies, 133 patients), and 7 days after surgery (SMD, 1.42; 95% CI, e1.34 to 4.18; 4 studies; 133
patients).
Sensitivity analysis revealed that MD in mouth opening between both arms was higher among
patients recruited in split-mouth trials than in those recruited in the parallel trials at 24 hours, 72
hours, and 7 days, but none of these were statistically signicant (eTable, available online at the
end of this article).
Effects of Ozone on Quality of Life
Only 2 trials
14,15
used the 14-item Oral Health Impact Prole to measure the quality of life of
included participants, the score of which ranges from 0 through 56, with higher score indicating
poor quality of life. Pooled analysis revealed that patients undergoing ozone treatment experienced
Table 2. Summary of the studies included.
TREATMENT GIVEN
STUDY
RANDOMIZATION
METHOD Intervention Group Comparison Group
OZONE APPLICATION
PROTOCOL
COINTERVENTION
THERAPY COMMON
TO BOTH GROUPS
Kazancioglu and
Colleagues,
14
2014
Not reported Ozone generator with high-
frequency, 7.5-cm, deep-
tissue probe
Group 1: Gallium aluminium
arsenide diode laser, 808
nm applied using handpiece
at 100 mW for a total of
120 s. Received 12 J low-
level laser therapy at the
insertion point of masseter
immediately after surgery
and at postoperative 24
hours, 72 hours, and 7 days
Group 2: Control
Applied extraorally at the
insertion point of masseter
immediately after surgery
and at postoperative 24
hours, 72 hours, and 7 days
with an intensity of 80% for
10 s
1,000 mg of amoxicillin
and 550 mg of naproxen
sodium orally and 0.2%
chlorhexidine mouthrinse
(1 min, 3 times daily)
for 1 wk
An ice pack was applied to
the surgery area for at least
30 min
Kazancioglu and
Colleagues,
15
2014
Split-mouth design
Envelopes
Ozone generator with high-
frequency, 7.5-cm, deep-
tissue probe
Sham ozone therapy Applied extraorally at the
insertion point of masseter
immediately after surgery
and at postoperative 24
hours, 72 hours, and 7 days,
with an intensity of 80% for
10 s
1,000 mg of amoxicillin
and 550 mg of naproxen
sodium orally and 0.2%
chlorhexidine mouthrinses
(1 min, 3 times daily)
for 1 wk
An ice pack was applied to
the surgery area for at least
30 min
Sivalingam and
Colleagues,
16
2016
Split-mouth design
Lottery method
Topical ozone, no systemic
antibiotics
Gauze dressing, systemic
antibiotics 500-mg
amoxicillin capsule and 400
mg of metronidazole (Flagyl)
3 times/d for 5 d
Ozone gel lled the entire
socket and as a smear on
the vertical limb of the
incision after careful
isolation of the surgical site
using a scoop for 2 min, 2
times/d for 3 d
Postoperative analgesics
(400-mg ibuprofen tablet,
333-mg paracetamol
tablet) for 2 d, 3 times/d
Glória and
Colleagues,
17
2020
Split-mouth design
Opaque and sealed
envelopes
Ozonized, double-distilled
water as irrigating solution
Double-distilled water as
irrigating solution
Ozone double-distilled
water used as constant
irrigation using a 10-cc glass
hypodermic syringe coupled
to a 10-mm steel needle
twice per day and after
surgery to irrigate the socket
1 500 mg of sodium
dipyrone tablet every 6 h
and 1 100 mg-nimesulide
tablet every 12 h for 3 d
JADA 152(10) nhttp://jada.ada.org nOctober 2021 847
Table 3. Outline of outcomes assessment.
STUDY PAIN SWELLING TRISMUS QUALITY OF LIFE ANALGESICS USE
Kazancioglu and Colleagues,
14
2014
Method Yes*Yes
†‡
Yes (maximum interincisal distance
between 2 opposite right central
incisors via vernier caliper)
Yes (OHIP-14
§
) Yes (count)
Time, d 24 hours, 72 hours,
and 7 days
0,
{
24 hours, 72 hours,
and 7 days
0, 24 hours, 72 hours,
and 7 days
0, 24 hours, 72 hours,
and 7 days
NA
#
Kazancioglu and Colleagues,
15
2014
Method Yes*Yes
†‡
Yes (maximum interincisal distance
between 2 opposite right central
incisors via vernier calipers)
Yes (OHIP-14) Yes (count)
Time, d 1, 3, 5, 7 0, 1, 3, 5, 7 0, 1, 3, 5, 7 0, 1, 3, 5, 7 NA
Sivalingam and Colleagues,
16
2016
Method Yes*Yes
†‡
** Yes (interincisal mouth opening
via vernier caliper)
No Yes (count)
Time, d 24 hours, 72 hours,
and 7 days
24 hours, 72 hours,
and 7 days
0, 24 hours, 72 hours,
and 7 days
NA 3-5
Glória and Colleagues,
17
2020
Method Yes*Yes
†‡
** Yes (interincisal mouth opening
via digital caliper)
No No
Time, d 1, 2, 3 0, 1, 2, 3, 7 0, 1, 2, 3, 7 NA NA
* Visual analog scale (0-10). Tragus to corner of mouth. Tragus to pogonion. § OHIP-14: 14-Item Oral Health Impact Prole. {Day 0: Preoperative. # NA: Not
applicable. ** Lateral canthus to angle of mandible.
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
Glória and Colleagues,17 2020 ++++++ +
Kazancioglu and Colleagues,14 2014 +++ +– – –
Kazancioglu and Colleagues,15 2014 +++++– –
Sivalingam and Colleagues,16 2016 ++++ +
Study
Domain
Figure 2. Risk-of-bias summary based on review authorsjudgments about each risk of bias for the included studies.
Green: Low risk of bias. Red: High risk of bias.
848 JADA 152(10) nhttp://jada.ada.org nOctober 2021
better quality of life than those in the control group, with MD ranging from 6 through 11 at the 3
times studied (Figure 6). Lower estimates of effect were observed at 24 hours (MD, e11.24; 95% CI,
e12.73 to e9.75; 2 studies, 80 patients), 72 hours (MD, e11.08; 95% CI, e12.08 to e10.08; 2
studies, 80 patients), and 7 days (MD, e6.85; 95% CI, e7.68 to e6.02; 2 studies, 80 patients) in
the intervention group. Results for sensitivity analysis were the same as the pooled estimates.
Heterogeneity: τ2 = 1.40; χ2
2 = 6.84, (P = .03); I2 = 71%
Test for overall effect: z = 2.80 (P = .005)
Heterogeneity: τ2 = 0.89; χ2
3 = 11.79, (P = .008); I2 = 75%
Test for overall effect: z = 4.53 (P < .00001)
Test for subgroup differences: χ2
1 = 0.64, (P = .42), I2 = 0%
Heterogeneity: Not applicable
Test for overall effect: z = 6.21 (P < .00001)
–3.3
–1.41
–3.37
0.5312
0.183
0.2563
73
60
60
133
53
60
60
113
73
60
60
133
–2.47 (–4.20 to –0.74)
–3.30 (–4.34 to –2.26)
–3.30 (–4.34 to –2.26)
–2.75 (–3.94 to –1.56)
–1.14 (–1.76 to –0.52)
–1.41 (–1.77 to –1.05)
–1.41 (–1.77 to –1.05)
–1.22 (–1.67 to –0.78)
–2.69 (–3.71 to –1.68)
–3.37 (–3.87 to –2.87)
–3.37 (–3.87 to –2.87)
–2.93 (–3.77 to –2.08)
73
133
60
60
53
113
60
60
73
133
60
60
Heterogeneity: τ2 = 0.45; χ2
2 = 6.78, (P = .03); I2 = 71%
Test for overall effect: z = 5.22 (P < .00001)
Heterogeneity: τ2 = 0.48; χ2
3 = 16.29, (P = .0010); I2 = 82%
Test for overall effect: z = 6.82 (P < .00001)
Test for subgroup differences: χ2
1 = 1.37, (P = .24), I2 = 27.0%
Heterogeneity: Not applicable
Test for overall effect: z = 13.15 (P < .00001)
Heterogeneity: τ2 = 0.16; χ2
1 = 4.37, (P = .04); I2 = 77%
Test for overall effect: z = 3.63 (P = .0003)
2.4.1 Split-mouth trials
Subtotal (95% CI)
2.4.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
2.5.1 Split-mouth trials
Subtotal (95% CI)
2.5.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
2.6.1 Split-mouth trials
00
0 Not estimable0Glória and Colleagues,17 2020
Subtotal (95% CI)
2.6.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
Heterogeneity: τ2 = 0.12; χ2
2 = 9.56, (P = .008); I2 = 79%
Test for overall effect: z = 5.41 (P < .00001)
Test for subgroup differences: χ2
1 = 0.55, (P = .46), I2 = 0%
Heterogeneity: Not applicable
Test for overall effect: z = 7.70 (P < .00001)
–3.8
–2.03
0.7647
0.1391
20
33
–3.80 (–5.30 to –2.30)
–2.03 (–2.30 to –1.76)
20
33
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
2.44 3.5162 20 2.44 (–4.45 to 9.33)20Glória and Colleagues,17 2020
–3.32
–2.18
0.3915
0.1971
20
33
–3.32 (–4.09 to –2.55)
–2.18 (–2.57 to –1.79)
20
33
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
–2.91 3.7001 20 –2.91 (–10.16 to 4.34)20Glória and Colleagues,17 2020
–1.52
–0.88
0.2907
0.0965
20
33
100.0
31.5
31.5
68.5
100.0
34.0
34.0
66.0
100.0
33.9
33.9
66.1
40.7
25.0
2.8
35.6
29.2
1.3
40.6
25.4 –1.52 (–2.09 to –0.95)
–0.88 (–1.07 to –0.69)
20
33
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
–100 –50
Favors (experimental) Favors (control)
500 100
–100 –50
Favors (experimental) Favors (control)
500 100
–100 –50
Favors (experimental) Favors (control)
500 100
Forest plot of comparison: Ozone versus placebo, outcome: Pain at 24 hours.
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
Forest plot of comparison: Ozone versus placebo, outcome: Pain at 72 hours
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CI
Study or Subgroup
Control
Forest plot of comparison: Ozone versus placebo, outcome: Pain at 7 days
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
A
B
C
Figure 3. Forest plots for comparison of ozone versus control: pain at 24 hours (A), 72 hours (B), and 7 days (C). IV: Independent variable. SE: Standard
error.
JADA 152(10) nhttp://jada.ada.org nOctober 2021 849
Analgesics use
Pooled analysis revealed that analgesic use was signicantly lower in the ozone group than in the
control group (weighted MD, e3.80; 95% CI, e4.38 to e3.22; I
2
¼0%). Results for sensitivity
analysis were the same as the pooled estimates as shown in Figure 7.
Safety of ozone treatment
No adverse effects were reported in any trials.
A
B
C
2.1.1 Split-mouth trials
Subtotal (95% CI)
Heterogeneity: τ2 = 5.93; χ2
2 = 90.60, (P < .00001); I2 = 98%
Test for overall effect: z = 0.82 (P = .41)
2.1.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
Heterogeneity: τ2 = 4.78; χ2
3 = 148.15, (P < .00001); I2 = 98%
Test for overall effect: z = 0.40 (P = .69)
Test for subgroup differences: χ2
1 = 3.89, (P = .05), I2 = 74.3%
Heterogeneity: Not applicable
Test for overall effect: z = 7.87 (P < .00001)
1.678
0.4817
1.1428
0.2132
0.1853
0.1974
73
60
60
133
73
60
60
133
73
60
60
133
100.0
25.4
25.4
74.6
100.0
25.7
25.7
74.3
100.0
25.6
25.6
74.4
–1.16 (–3.95 to 1.63)
1.68(1.26 to 2.10)
1.68(1.26 to 2.10)
–0.44 (–2.61 to 1.73)
–1.34 (–2.96 to 0.28)
0.48 (0.12 to 0.84)
0.48 (0.12 to 0.84)
–0.87 (–2.31 to 0.56)
0.48 (–2.64 to 3.60)
1.14 (0.76 to 1.53)
1.14 (0.76 to 1.53)
0.63 (–1.42 to 2.69)
73
133
60
60
73
133
60
60
73
133
60
60
2.2.1 Split-mouth trials
Subtotal (95% CI)
Heterogeneity: τ2 = 7.44; χ2
2 = 102.65, (P < .00001); I2 = 98%
Test for overall effect: z = 0.30 (P = .76)
2.2.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
Heterogeneity: τ2 = 4.26; χ2
3 = 130.85, (P < .00001); I2 = 98%
Test for overall effect: z = 0.60 (P = .55)
Test for subgroup differences: χ2
1 = 0.17, (P = .68), I2 = 0%
Heterogeneity: Not applicable
Test for overall effect: z = 5.79 (P < .00001)
2.3.1 Split-mouth trials
Subtotal (95% CI)
Heterogeneity: τ2 = 1.93; χ2
2 = 35.82, (P < .00001); I2 = 94%
Test for overall effect: z = 1.62 (P = .10)
2.3.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
Heterogeneity: τ2 = 2.04; χ2
3 = 76.42, (P < .00001); I2 = 96%
Test for overall effect: z = 1.20 (P = .23)
Test for subgroup differences: χ2
1 = 4.64, (P = .03), I2 = 78.5%
Heterogeneity: Not applicable
Test for overall effect: z = 2.60 (P = .009)
Glória and Colleagues,17 2020 –0.195 0.3171 20 25.1 –0.20(–0.82 to 0.43)20
3.924
–2.5229
0.5599
0.3345
20
33 25.2
24.0 3.92 (2.83 to 5.02)
–2.52 (–3.18 to –1.87)
20
33
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
0.1228 0.3166 20 25.2 0.12 (–0.50 to 0.74)20
Glória and Colleagues,17 2020
–1.0765
–2.9122
0.3407
0.3591
20
33 24.6
24.7 –1.08 (–1.74 to –0.41)
–2.91 (–3.62 to –2.21)
20
33
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
–0.0606 0.3163 20 24.9 –0.06 (–0.68 to 0.56)20Glória and Colleagues,17 2020
–100 –50
Favors (experimental) Favors (control)
500 100
–100 –50
Favors (experimental) Favors (control)
500 100
–100 –50
Favors (experimental) Favors (control)
500 100
Forest plot of comparison: Ozone versus placebo, outcome: Swelling at 24 hours.
Experimental
Std. Mean Difference SE Total Total Weight, %
Std. Mean Difference
IV, Random, 95% CI
Std. Mean Difference
IV, Random, 95% CI
Study or Subgroup
Control
Forest plot of comparison: Ozone versus placebo, outcome: Swelling at 72 hours
Experimental
Std. Mean Difference SE Total Total Weight, %
Std. Mean Difference
IV, Random, 95% CI
Std. Mean Difference
IV, Random, 95% CI
Study or Subgroup
Control
Forest plot of comparison: Ozone versus placebo, outcome: Swelling at 7 days
Experimental
Std. Mean Difference SE Total Total Weight, %
Std. Mean Difference
IV, Random, 95% CI
Std. Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
1.0169
–4.3574
0.3381
0.4621
20
33 24.5
25.0 1.02 (0.35 to 1.68)
–4.36 (–5.26 to –3.45)
20
33
Figure 4. Forest plots for comparison of ozone versus control: swelling at 24 hours (A), 72 hours (B), and 7 days (C). IV: Independent variable. SE:
Standard error. Std: Standard.
850 JADA 152(10) nhttp://jada.ada.org nOctober 2021
Quality of evidence
Only randomized, double-blind, placebo-controlled trials were included in our review. All of the
included trials reported the studied outcomes along with dispersion. Signicant heterogeneity (I
2
>
75%) was identied in our analyses. This heterogeneity, the relatively small number of participants,
and the wide CIs of few outcomes resulted in a GRADE evidence certainty assessment of moderate
to low for most of our analyses. Only 1 split-mouth trial
15
and 1 parallel trial
14
assessed quality of
life, making it difcult to draw robust conclusions from this analysis. Owing to the limited number
of trials, publication bias could not be assessed using a funnel plot, and this issue was addressed by
means of citation searching.
Heterogeneity: τ2 = 10.88; χ2
2 = 11.27, (P = .004); I2 = 82%
Test for overall effect: z = 1.93 (P = .05)
Heterogeneity: τ2 = 19.67; χ2
3 = 41.83, (P < .00001); I2 = 93%
Test for overall effect: z = 1.15 (P = .25)
Test for subgroup differences: χ2
1 = 3.99, (P = .05), I2 = 74.9%
Heterogeneity: Not applicable
Test for overall effect: z = 0.56 (P = .58)
–0.5 0.8993
73
60
60
133
73
133
60
60
100.0
27.8
27.8
72.2 4.23 (–0.07 to 8.53)
–0.50 (–2.26 to 1.26)
–0.50 (–2.26 to 1.26)
2.74 (–1.93 to 7.41)
2.7.1 Split-mouth trials
Subtotal (95% CI)
2.7.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
–100 –50
Favors (experimental) Favors (control)
500 100
3
7.66
1.3928
0.9116
20
33
20
33 27.7
26.3 3.00 (0.27 to 5.73)
7.66 (5.87 to 9.45)
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
–0.18 3.3913 20 20 18.2 –0.18 (–6.83 to 6.47)Glória and Colleagues,17 2020
Forest plot of comparison: Ozone versus placebo, outcome: Mouth Opening at 24 hours
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
0.9 1.1191
73
60
60
133
73
133
60
60
100.0
29.5
29.5
70.5 3.64 (–0.12 to 7.40)
0.90 (–1.29 to 3.09)
0.90 (–1.29 to 3.09)
2.77 (–0.63 to 6.17)
Heterogeneity: τ2 = 7.31; χ2
2 = 6.62, (P = .04); I2 = 70%
Test for overall effect: z = 1.90 (P = .06)
Heterogeneity: τ2 = 8.93; χ2
3 = 16.40, (P = .0009); I2 = 82%
Test for overall effect: z = 1.60 (P = .11)
Test for subgroup differences: χ2
1 = 1.52, (P = .22), I2 = 34.4%
Heterogeneity: Not applicable
Test for overall effect: z = 0.80 (P = .42)
2.8.1 Split-mouth trials
Subtotal (95% CI)
2.8.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
–100 –50
Favors (experimental) Favors (control)
500 100
1.9
6.28
1.8102
0.8936
20
33
20
33 30.9
24.6 1.90 (–1.65 to 5.45)
6.28 (4.53 to 8.03)
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
0.65 3.3577 20 20 14.9 0.65 (–5.93 to 7.23)Glória and Colleagues,17 2020
Forest plot of comparison: Ozone versus placebo, outcome: Mouth Opening at 72 hours
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
0.2 0.664
73
60
60
133
73
133
60
60
100.0
33.4
33.4
66.6 2.07 (–1.21 to 5.36)
0.20 (–1.10 to 1.50)
0.20 (–1.10 to 1.50)
1.42 (–1.34 to 4.18)
Heterogeneity: τ2 = 5.03; χ2
2 = 5.08, (P = .08); I2 = 61%
Test for overall effect: z = 1.24 (P = .22)
2.9.1 Split-mouth trials
Subtotal (95% CI)
2.9.2 Parallel trials
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Total (95% CI)
Heterogeneity: τ2 = 5.49; χ2
3 = 15.85, (P = .001); I2 = 81%
Test for overall effect: z = 1.01 (P = .31)
Test for subgroup differences: χ2
1 = 1.08, (P = .30), I2 = 7.6%
Heterogeneity: Not applicable
Test for overall effect: z = 0.30 (P = .76)
–100 –50
Favors (experimental) Favors (control)
500 100
1.3
4.16
1.986
0.808
20
33
20
33 32.3
21.0 1.30 (–2.59 to 5.19)
4.16 (2.58 to 5.74)
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
–1.97 3.0611 20 20 13.3 –1.97 (–7.97 to 4.03)
Glória and Colleagues,17 2020
Forest plot of comparison: Ozone versus placebo, outcome: Mouth Opening at 7 days
Experimental
Mean Difference SE Total Total Weight, %
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CIStudy or Subgroup
Control
A
B
C
Figure 5. Forest plots for comparison of ozone versus control: trismus or mouth opening at 24 hours (A), 72 hours (B), and 7 days (C). IV: Independent
variable. SE: Standard error.
JADA 152(10) nhttp://jada.ada.org nOctober 2021 851
DISCUSSION
Our meta-analysis, which included 4 RCTs
14-17
and a total sample of 133 patients, evaluated the
efcacy of ozone in reducing postoperative complications after IMTM extraction. Statistically
signicant positive effects that were small showed improvement in pain and quality of life, and
reduction in number of analgesics consumed by the patients treated with ozone. However, the effect
of ozone on trismus and swelling after IMTM was statistically insignicant. Adverse events were not
found in any of the studies, which suggests that ozone appears to be a safe therapy. The quality of
evidence was moderate to low and should be interpreted with caution because the effects estimates
might have been inuenced by several factors, including variable ozone regimens and patient
factors, especially pain relief, which is a subjective outcome and could be explained in part as
placebo effect. The difculty of blinding the participants is associated with high risk of performance
bias.
28
These 4 trials
14-17
were conducted across varied geographical locations (that is, Brazil, India, and
Turkey), which might support the applicability of our ndings across different practice settings and
patient populations. The populations studied in our review were comparable, with similar de-
mographics, mean surgical times, and difculty indexes. Furthermore, the 3 split-mouth studies
15-17
had crossover trials with sufcient washout periods (2-4 weeks), reducing patient factors acting as
confounding variables. Nevertheless, there have been conicting opinions on the split-mouth
design used in oral health care research. In a meta-epidemiologic study, Qiao and colleagues
29
concluded that split-mouth designs are similar to parallel designs if executed and analyzed prop-
erly. The split-mouth design used in our meta-analysis met the prerequisite that disease is stable with
Heterogeneity:τ2 = 0.00; χ2
1 = 0.68, (P = .41); I2 = 0%
Test for overall effect: z = 16.20 (P < .00001)
–100 –50
Favors (experimental) Favors (control)
500 100
Heterogeneity: τ2 = 0.00; χ2
1 = 0.95, (P = .33); I2 = 0%
Test for overall effect: z = 21.67 (P < .00001)
Mean Difference
IV, Random, 95% CI
Heterogeneity: τ2 = 0.00; χ2
1 = 0.41, (P = .52); I2 = 0%
Test for overall effect: z = 14.80 (P < .00001)
Test for subgroup differences: χ2
2 = 51.07, (P < .00001), I2 = 96.1%
1.4.1 At 7 days
Kazancioglu and Colleagues,14 2014
Subtotal (95% CI)
1.4.3 At 24 hours
Kazancioglu and Colleagues,15 2014
1.4.2 At 72 hours
Kazancioglu and Colleagues,14 2014
Subtotal (95% CI)
Kazancioglu and Colleagues,15 2014
Subtotal (95% CI)
Glória and Colleagues,17 2020
Kazancioglu and Colleagues,14 2014
Sivalingam and Colleagues,16 2016
Kazancioglu and Colleagues,15 2014
Study or Subgroup
100.0
72.1
27.9
100.0
73.4
26.6
Weight, %
Experimental
13.72
13.88
18.24
19.34
Mean
1.29
1.28
0.53
0.56
SD
20
60
80
20
60
80
Total
20.01
20.95
30.15
30.12
Mean
3.34
3.64
4.4
4.59
SD
20
60
80
20
60
80
Total
–6.29 (–7.86 to –4.72)
–7.07 (–8.05 to –6.09)
–6.85 (–7.68 to –6.02)
–11.91 (–13.85 to –9.97)
–10.78 (–11.95 to –9.61)
–11.08 (–12.08 to –10.08)
100.080 80 –11.24 (–12.73 to –9.75)
0 0 0 0 0 0 Not estimable
69.5
30.521.24
21.34
0
3.25
4.05
0
20
60
0
33.22
32.26
0
5.22
5.78
0
20
60
0
–11.98 (–14.67 to –9.29)
–10.92 (–12.71 to –9.13)
Not estimable
Mean Difference
IV, Random, 95% CI
Control
Figure 6. Forest plot for comparison of ozone versus control: quality of life at 24 hours, 72 hours, and 7 days. IV: Independent variable. SD: Standard
deviation.
Mean Difference
IV, Random, 95% CI
–100 –50
Favors (experimental) Favors (control)
500 100
100.0
Weight, %
Heterogeneity: τ2 = 0.00; χ2
1 = 0.00, (P = 1.00); I2 = 0%
Test for overall effect: z = 12.87 (P < .00001)
Experimental
Mean SD Total
113
Mean SD Total
113
1 0 33 1.32 0.48 33
25.0
4.6 2.1 20 8.4 1.6 20
75.0
Mean Difference
IV, Random, 95% CI
–3.80 (–4.38 to –3.22)
Not estimable
–3.80 (–4.96 to –2.64)
–3.80 (–4.47 to –3.13)
4.6 2.1 60 8.4 1.6 60
Study or Subgroup
Glória and Colleagues,17 2020
Kazancioglu and Colleagues,14 2014
Total (95% CI)
Kazancioglu and Colleagues,15 2014
Control
Figure 7. Forest plot for comparison of ozone versus control: total analgesic use. IV: Independent variable. SD: Standard deviation. SE: Standard error.
852 JADA 152(10) nhttp://jada.ada.org nOctober 2021
no period effect and no carryover effect, with a sufcient washout phase of 2 through 4 weeks. In
theory, any differences in outcomes between the 2 approaches are only due to their properties and
not participant-related factors.
One possible limitation could be probability of publication bias, which we tried to minimize by
means of searching all relevant online sources. It is still possible that some unpublished data or
articles in noneEnglish-language articles were missed, but this should not result in large bias, as
suggested by Moher and colleagues.
30
Although all 4 studies
14-17
had positive results as adjunctive therapies, this needs to be inter-
preted in the shadow of a high level of bias owing to small sample size. The 2 studies by Kazancioglu
and colleagues
14,15
have exactly the same population demographics, mean surgical time, and total
number of analgesics consumed, in totally different study designs, which is unexplainable and is an
independent nding that might question the validity of this meta-analysis. Furthermore, the
included studies used different ozone regimens in terms of states of matter and point and place of
application, which can potentially affect the outcomes studied and could be a cause of heterogeneity
of our meta-analysis. The small number of RCTs identied for inclusion in our review further
obviated the possibility of subgroup analysis.
There have been a few RCTs evaluating the efcacy of ozone therapy in some challenging
clinical scenarios, such as diabetic foot ulcers, second-degree burns, alveolar osteitis, and
bisphosphonate-related osteonecrosis of the jaw.
31-34
Ahmedi and colleagues
13
found an incidence
of 3.3% alveolar osteitis with use of prophylactic intra-alveolar ozone therapy compared with
16.67% with control participants in IMTM extractions. Dawdy and colleagues,
20
in their systematic
review of 21 RCTs, found that low-level laser therapy had negligible benet and no adverse out-
comes. Our meta-analysis of 4 low-quality studies of ozone with no documented adverse effects
paves the way for future research to build robust evidence for or against ozone therapy as an
adjunctive in after IMTM extractions.
Our meta-analysis revealed several limitations that will guide future research in the form of high-
quality RCTs of ozone with placebos and possibly low-level laser therapy with larger sample size.
The choice of ozone regimen should be an important part of clinical decision making, but the
evidence from head-to-head trials comparing different ozone regimens for third-molar surgery is
scarce, and a pragmatic recommendation for a specic prescription requires additional robust
research to standardize the ozone therapy regimen to remove the heterogeneity in the intervention
delivered. Follow-up planning at specic times in a 1-week interval, along with standardization of
swelling evaluation, would help us analyze the outcomes in a reproducible manner. Split-mouth
designs have the advantage of optimizing resources if strict rules of implementation, statistical
analysis, and reporting are followed.
CONCLUSIONS
Evidence suggests that adjuvant ozone application can offer some benet for reducing pain,
improving quality of life, and decreasing mean analgesic intake after IMTM extraction, but it is not
effective for reducing facial swelling and trismus. Considering the low quality of available evidence,
adequately powered, double-blind, placebo-controlled trials with appropriate randomization, allo-
cation concealment, and blinding of outcomes assessment, along with standardization of ozone
therapeutic regimen are needed in the future to substantiate efcacy of ozone after IMTM
extraction. n
SUPPLEMENTAL DATA
Supplemental data related to this article can be found at: https://doi.org/10.1016/j.adaj.2021.05.006.
Dr. Chaudhry is an associate professor, Oral and Maxillofacial Surgery,
Department of Dentistry, All India Institute of Medical Sciences, Jodhpur,
Rajasthan, India.
Dr. Rustagi is an associate professor, Department of Community Medi-
cine and Family Medicine, All India Institute of Medical Sciences, Jodhpur,
Rajasthan, India.
Dr. Bali is a professor, Department of Oral and Maxillofacial Surgery,
DAV Dental College, Yamunanagar, Haryana, India.
Dr. Khatana is a senior resident, Oral and Maxillofacial Surgery,
Department of Dentistry, All India Institute of Medical Sciences, Jodhpur,
Rajasthan, India.
JADA 152(10) nhttp://jada.ada.org nOctober 2021 853
Dr. Shailendra Kumar is a junior resident, Oral and Maxillofacial Surgery,
Department of Dentistry, All India Institute of Medical Sciences, Jodhpur,
Rajasthan, India.
Dr. Kaur is a senior resident, Oral and Maxillofacial Surgery, Department
of Dentistry, All India Institute of Medical Sciences, Basni, Jodhpur, Rajas-
than, 342005, India., email amanjotkaur1992@yahoo.com. Address cor-
respondence to Dr. Kaur.
Dr. Pravin Kumar is a professor and head, Department of Dentistry, All
India Institute of Medical Sciences, Jodhpur, Rajasthan.
Disclosures. None of the authors reported any disclosures.
The authors thank the trial authors who responded to us for the missing
data.
1. Bui CH, Seldin EB, Dodson TB. Types, frequencies,
and risk factors for complications after third molar
extraction. J Oral Maxillofac Surg. 2003;61(12):1379-1389.
2. Shugars DA, Gentile MA, Ahmad N, et al. Assess-
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854 JADA 152(10) nhttp://jada.ada.org nOctober 2021
SEARCH STRATEGY
The search strategy used was the following: (Mandibular[MeSH Terms]) OR mandibular[Title/
Abstract]) OR third molar[MeSH Terms]) OR third molar[Title/Abstract]) OR impaction[MeSH
Terms]) OR impaction[Title/Abstract]) OR removal[Title/Abstract]) OR removal[MeSH Terms])
OR wisdom tooth[Title/Abstract]) OR wisdom tooth[MeSH Terms])) AND ((ozone*
[Title/Abstract]) OR ozone*[MeSH Terms]) AND (Humans[Mesh])
MeSH: Medical subject heading.
eTable. Ozone treatment compared with placebo for impacted molar.
CERTAINTY
ASSESSMENT NO. OF PATIENTS EFFECT
NO. OF
STUDIES
STUDY
DESIGN
RISK OF
BIAS Inconsistency Indirectness Imprecision
OTHER
CONSIDERATIONS
Ozone
Treatment Placebo
Relative
(95% CI)
Absolute
(95% CI) CERTAINTY
4Randomized
trials
Not
serious
Serious*Not serious Serious
Publication bias
strongly suspected
133 133 NA
§
SMD
{
1.44
Lower (3.06 to
0.18)
Very low
4Randomized
trials
Not
serious
Serious*Not serious Serious
Publication bias
strongly suspected
133 133 NA SMD 0.09
Lower (1.57 to 1.4)
Very low
4Randomized
trials
Not
serious
Serious*Not serious Serious
Publication bias
strongly suspected
133 133 NA SMD 0.91
Lower (2.56 to
0.74)
Very low
4Randomized
trials
Not
serious
Serious*Not serious Serious
Publication bias
strongly suspected
133 133 NA MD
#
1.42
Higher (1.34 to
4.18)
Very low
4Randomized
trials
Not
serious
Serious
Not serious Serious
Publication bias
strongly suspected
133 133 NA MD 2.77
Higher (0.63 to
6.17)
Very low
4Randomized
trials
Not
serious
Serious*Not serious Serious
Publication bias
strongly suspected
133 133 NA MD 2.74
Higher (1.93 to
7.41)
Very low
2Randomized
trials
Serious** Not serious Not serious Not
serious
††
Publication bias
strongly suspected
80 80 NA MD 6.85 lower
(7.68 to 6.02)
Low
2Randomized
trials
Serious** Not serious Not serious Not
serious
††
Publication bias
strongly suspected
80 80 NA MD 11.08
Lower (12.08 to
10.08)
Low
2Randomized
trials
Serious** Not serious Not serious Not serious Publication bias
strongly suspected
80 80 NA MD 11.24
Lower (12.73 to
9.75)
Low
3Randomized
trials
Serious** Serious*Not serious Serious
Publication bias
strongly suspected
113 113 NA MD 1.22 lower
(1.67 to 0.78)
Very low
4Randomized
trials
Serious** Serious*Not serious Not serious Publication bias
strongly suspected
133 133 NA MD 2.93 lower
(3.77 to 2.08)
Very low
4Randomized
trials
Serious** Serious*Not serious Not serious Publication bias
strongly suspected
133 133 NA MD 2.75 lower
(3.94 to 1.56)
Very low
2Randomized
trials
Serious** Not serious Not serious Not serious Publication bias
strongly suspected
80 80 NA MD 0 e3.80 (4.38
to 3.22)
Low
* Unexplained statistical heterogeneity; however, the estimates of effect are not clinically different. Sample size or number of events does not meet the optimal
information size as calculated, the CIs include the possibility of a small or no effect. Small number of studies with small sample size with most positive results. § NA:
Not applicable. {SMD: Standardized mean difference. # MD: Mean difference. ** Investigators in most studies did not report methods for sequence generation and
allocation concealment or the reporting was unclear. Assessment of subjective outcome is likely to be inuenced in trials even with blinding of participants and
outcomes, and had high risk of bias for selective outcomes reporting. †† Sample size or number of events does not meet the optimal information size as calculated.
JADA 152(10) nhttp://jada.ada.org nOctober 2021 854.e1
... On the other hand, nonpharmacological complementary interventions are proposed to enhance pain relief, and reduce analgesic use, mitigating the unwanted effects and contraindications of allopathic medications [6][7][8][9][10][11][12]. is goal is especially important in reducing or eliminating the use of opioid analgesics. Furthermore, nonpharmacologic methods may improve the outcomes of typical anti-inflammatory medications used after third molar surgery [8]. ...
... Several nonpharmacological complementary methods have been reported in evidence-based systematic reviews with or without meta-analyses for controlling postoperative morbidities related to third molar removal. ey include the application of low-level laser therapy (LLLT) [13], cryotherapy [11], application of platelet-rich fibrin (PRF) [12], application of hyaluronic acid [10], ozone therapy [7], application of drainage [9], and kinesio taping (sports tapes) [8]. ...
... A total of 659 papers were retrieved from 4 main electronic databases and Google Scholar. Twenty-two eligible published meta-analyses were considered for inclusion in this umbrella review after titles and abstracts were screened and duplicate metaanalyses were removed [7,9,12]; do [6,8,10,11]. ...
Article
Full-text available
Objectives: To provide a nonbiased, complete assessment of what the evidence from meta-analyses informs us about complementary and nonpharmacological treatment options for the management of pain after third molar surgery, as well as highlight any discordancy, gaps, or lack of evidence among meta-analyses. Methods: The quality of the included systematic reviews was assessed using the ROBIS tool. Corrected covered area (CCA) was calculated for pairs of similar meta-analyses to identify the amount of overlap. Reviews that were the most recent, comprehensive, and had adequate quality were considered for analyses when reviews showed a high overlap. In cases with a low amount of overlap among meta-analyses, all eligible studies were included. Also, citation matrices were constructed to address overlap. A network meta-analytical approach was adopted to rank different interventions. Results: Ten meta-analyses were included for quantitative synthesis. The quantitative analysis revealed that platelet-rich fibrin and its derivatives as well as ozone therapy reduce early and late pain better than the other complementary interventions compared to control (no complementary intervention). Conclusions: Despite the shortcomings of included meta-analyses, consolidated evidence suggests that platelet-rich-fibrin and its derivatives as well as ozone therapy outperform the other nonpharmacological complementary interventions in reducing early and late postsurgical pain following third molar extraction. However, the results should be interpreted with caution due to an unclear risk of bias and lack of firm evidence in the included meta-analyses. Moreover, there is a need for a standard protocol for the application of nonpharmacological complementary interventions.
... The results of the first and second phases were compared, looking for fields of application already investigated or not in a pediatric population [1,9,16,[30][31][32][33][34][35][36][37]. In Table 2, the main results of the comparison of the literature are shown. ...
... Sensitivity of enamel developmental defects [1,40] Acceleration of healing (dental fistula or surgery extraction) [26,30,31] Herpes simplex infection or candida infection [9,32,33] Aphthous stomatitis [34] Pain management [16,35,36] Dental injuries or regenerative endodonticprocedures [37,38] The references of the studies were also analyzed to find other articles to be included. The authors chose to perform a narrative literature review because of the heterogeneity or insufficiency of the results. ...
Article
Full-text available
The therapeutic use of ozone has been suggested for a long time in general dentistry and paediatric dentistry for its antimicrobial, virucidal, disinfectant, and biocompatible properties. Ozone has also anti-inflammatory, analgesic, and immunostimulant properties, and it promotes tissue regeneration. Dental treatment in children is often complex and ozone could support the clinician to enhance the approach and prognosis with young patients, non-cooperant children, or special needs patients. The efficiency of ozone will certainly increase if studies continue to show positive outcomes in a growing number of dental paediatric conditions. This review explores the recent literature of ozone therapy in paediatric dentistry and suggests fields of application for future randomized controlled trials (RCTs).
Article
Objective: To evaluate the effectiveness of the use of adjuvant ozone therapy in the healing process of wounds resulting from periodontal and peri-implant surgical procedures by answering the following focused question: "Can adjuvant ozone therapy improve wound healing outcomes related to periodontal and peri-implant surgical procedures?". Method and materials: MEDLINE (via PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched, without language restriction, for peer-reviewed articles published until 23 March 2022, in addition to manual search. Only controlled clinical trials (randomized or not) were considered. The risk of bias was evaluated by the Cochrane risk-of-bias tool for RCTs - version 1 (RoB1). Data were pooled into evidence tables and a descriptive summary was presented. Results: Of the 107 potentially eligible records, only seven studies were included. Four addressed free/deepithelialized gingival grafts with a palatal donor area, two evaluated implant sites, and one comprised gingivectomy and gingivoplasty. A total of 225 patients were evaluated in the included studies, considering control and test groups (ozone and other adjuvant therapies for comparison). Ozone therapy had a positive effect on outcomes directly or indirectly related to periodontal/peri-implant surgical wound healing. Furthermore, it could also increase the stability of immediately loaded single implants installed in the posterior mandible. Conclusion: In general, ozone therapy seems to both accelerate the healing processes of periodontal/peri-implant wounds and increase the secondary stability of dental implants; however, considering the limited evidence available and the risk of bias in the included studies (none classified as low risk), a definitive conclusion cannot be drawn.
Article
Full-text available
Background: This study aimed to evaluate the efficacy of ozonized water on pain, oedema and trismus after impacted third molar mandibular surgeries when compared to double distilled water. A randomized triple blind trial was conducted. Methods: Patients with third molars class II-B of Pell-Gregory were included, and surgical extraction was performed. Irrigation was done with ozonized (group 1) or double distilled water (group 2). The type of irrigation and the side to be operated were randomized. Neither the patients nor the operator or evaluator were aware of the irrigation solution. Pain, oedema and trismus were evaluated at baseline, 24-h, 48-h, 72-h and 7-days after treatment. The data were evaluated by Friedman, Wilcoxon, Mann-Whitney tests, and size effect. Results: It was included 8 men and 12 women, with a mean age of 20.9y.o. The initial pain mean was 7.94 (±12.81) (group 1) and 5.50 (±9.12) (group 2) (p > 0,05). There was a statistically significant reduction of pain, oedema and trismus in intragroup analysis (p < 0.05). There was no statistically significant difference (p > 0.05) when comparing the oedema and trismus between groups. The size effect ranged from small (0.23) to large (1.29). Conclusions: It was concluded that ozonized water was compatible as irrigation method, not inferior to double distilled water, and had satisfactory effects on management of pain, oedema and trismus after surgical removal of the third molar. Trial registration: This clinical trial was registered in ClinicalTrials.gov NCT03501225 on April 18, 2018.
Article
Full-text available
Pain, swelling, and trismus are known sequelae of third molar surgery that can significantly affect the individual's quality of life (QOL). These should be minimized to improve QOL. The purpose of this study was to compare the effects of the preoperative submucosal administration of equivalent doses of two commonly used steroids on these postoperative sequelae. A randomized controlled clinical trial was conducted involving 60 subjects requiring the removal of impacted mandibular third molars. Extraction cases with a similar difficulty index were included. The participants were allocated randomly to three groups: the placebo group received normal saline injection (control), while the 8mg dexamethasone group and 40mg methylprednisolone group received submucosal injections of these steroids preoperatively. Each participant was assessed for postoperative pain, swelling, and trismus, along with a subjective assessment of QOL through a structured questionnaire. The participants administered dexamethasone showed significant reductions in pain and trismus compared to the control group (P<0.05). Submucosal injection of dexamethasone was found to be superior to methylprednisolone only in terms of the reduction in swelling. QOL was minimally affected in patients administered dexamethasone as compared to methylprednisolone and control subjects. The preoperative submucosal use of steroids can be considered an effective, safe, and simple therapeutic strategy to reduce swelling, pain, and trismus after the surgical removal of impacted mandibular third molars.
Article
Full-text available
The emphasis on oral health-related quality of life (OHRQoL) among patients is increasing. This study was conducted to identify the risk factors for the impairment of OHRQoL at one week after mandibular third molars (M3Ms) removal. A sample of 330 third molars was included and followed up one week postoperatively. Postoperative Symptom Severity scale (PoSSe) was representative of the primary outcome. Descriptive, bivariable, and multiple logistic regression analysis were performed. According to the logistic regression model, female (OR 1.70, 95% CI 1.03-2.80, P=0.037), smokers (OR 2.10, 95% CI 1.23-3.59, P=0.007), a higher Pell-Gregory Class level (OR 1.80, 95% CI 1.01-3.21, P=0.047 for Pell-Gregory class II and OR 3.02, 95% CI 1.38-6.57, P=0.006 for Pell-Gregory class III), prolonged operative time (OR 1.04, 95% CI 1.02-1.07, P=0.001), and preoperative symptoms (OR=2.01; 95% CI 1.17-3.45, P=0.011) were associated with higher scores on the PoSSe questionnaire. Therefore, Smokers, operative time, preoperative symptoms, and the Pell-Gregory Class are independent risk factors for the deterioration of OHRQoL. These findings may help clinicians to select an appropriate strategy to prevent deterioration of quality of life after M3Ms removal.
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The revised edition of the Handbook offers the only guide on how to conduct, report and maintain a Cochrane Review ? The second edition of The Cochrane Handbook for Systematic Reviews of Interventions contains essential guidance for preparing and maintaining Cochrane Reviews of the effects of health interventions. Designed to be an accessible resource, the Handbook will also be of interest to anyone undertaking systematic reviews of interventions outside Cochrane, and many of the principles and methods presented are appropriate for systematic reviews addressing research questions other than effects of interventions. This fully updated edition contains extensive new material on systematic review methods addressing a wide-range of topics including network meta-analysis, equity, complex interventions, narrative synthesis, and automation. Also new to this edition, integrated throughout the Handbook, is the set of standards Cochrane expects its reviews to meet. Written for review authors, editors, trainers and others with an interest in Cochrane Reviews, the second edition of The Cochrane Handbook for Systematic Reviews of Interventions continues to offer an invaluable resource for understanding the role of systematic reviews, critically appraising health research studies and conducting reviews.
Article
Background: The aim of this systematic review and meta-analysis was to evaluate the efficacy of cryotherapy in reducing pain, trismus, and facial swelling in patients undergoing third-molar surgery. Types of studies reviewed: The authors searched for randomized clinical trials in PubMed, Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Google Scholar, and OpenThesis. Eligibility criteria were population: patients submitted to removal of impacted third molars; intervention and comparison: postoperative cryotherapy versus no cold therapy; and outcomes: primary outcome was postoperative pain, and secondary outcomes were facial swelling and trismus. Eligible studies must have reported at least 1 of the outcomes of interest. After extracting data and assessing quality, the authors performed the meta-analyses. Results: The authors included 6 studies in the quantitative synthesis analysis. Differences in pain intensity were found on postoperative day 2 (weighted mean difference, -0.72; 95% confidence interval, -1.45 to 0.01; P = .05) and postoperative day 3 (weighted mean difference, -0.36; 95% confidence interval, -0.59 to -0.13; P = .002). No evidence was found that cryotherapy was effective in reducing trismus and facial swelling. The quality of evidence was graded as low. Conclusions and practical implications: Evidence suggests that cryotherapy may have a small benefit in reducing pain after third-molar surgery, but it is not effective on facial swelling and trismus. Owing to the lack of standardization of cold application, effective evidence-based treatment protocols for cryotherapy after third-molar surgery still need to be established.
Article
The aim of this study was to compare the effects of acupuncture and placebo acupuncture on the control of pain, oedema, and trismus following the extraction of third molars and on the control of preoperative anxiety. Sixteen patients (mean age 22.5±3.45years) each underwent four acupuncture sessions, one prior to each surgery and the others at 24, 48, and 72hours after each surgery (left and right tooth). Oedema was determined using measurements of the face and trismus was determined by maximum mouth opening at baseline and at 24, 48, 72hours and 7days following surgery. Postoperative pain was evaluated by the patients using a visual analogue scale (VAS) at 24, 48, and 72hours following surgery. Anxiety was evaluated using the State-Trait Anxiety Inventory and a VAS at baseline and before and after acupuncture prior to surgery. The statistical analysis was performed using the paired t-test and Wilcoxon test. Acupuncture showed a better performance in the control of oedema at 48hours (P=0.026), 72hours (P=0.046), and 7days (P=0.040) when compared to placebo. There was no statistically significant difference between the acupuncture and placebo groups in the control of pain, trismus, or anxiety.
Article
The aim of this systematic review was to identify randomized, placebo-controlled clinical trials investigating the effectiveness of corticosteroids in the control of pain, oedema, and trismus following third molar surgery, and to analyse the effects of the type of drug administered and the time and route of drug administration on the outcomes of interest. Searches were performed in the PubMed, Scopus, and Cochrane Library databases. This review was structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The search identified 1223 studies. After assessing eligibility based on the inclusion and exclusion criteria, 17 studies were selected for the qualitative analysis (a total of 730 patients aged 15-45 years). Ten studies were included in the meta-analysis, which was performed using Review Manager software. The corticosteroids were effective in controlling pain (P=0.002; mean difference -17.38, 95% confidence interval -24.81 to -9.95) and trismus (P<0.00001; mean difference 6.10, 95% confidence interval 3.42 to 8.77). With the exception of the submucosal route, the route of administration did not appear to affect the outcomes. The administration of a corticosteroid in the preoperative phase was superior to its use in the postoperative phase for the control of trismus.
Article
Purpose Dry socket is one of the most common complications following dental extraction. Although blood clot disintegration is known to be the cause of the condition, an agreement is lacking regarding the relative merits of various treatment methods. Despite the fact that ozone is one recommended therapy, the literature is deprived of any comparative study for the different forms of ozone delivery. The aim of the current study therefore was to evaluate the efficacy of different forms of ozone as a treatment for this condition. Methods A total of 1521 patients were categorized into four groups (I, II, III and IV) according to pain severity depending on the need and the response to analgesics (mild, moderate, severe or agonizing, respectively). Each group was randomly and blindly divided into three subgroups according treatment method: Oleozon (Ole) which is an ozonized olive oil, ozonized water (OW), ozone gas (O3). Results While Ole, OW and O3 were curative in groups I and II, only O3 was curative for groups III and IV. OW was palliative in group IV. Only O3 was definitive therapy for all groups. Conclusion Ozone in the gaseous form is the most potent form of ozone therapy. Although ozonized oil shows the weakest form, OW had an intermediate potency.
Article
Background The authors updated a previously published systematic review to assess the effects of low-level laser therapy (LLLT) on reducing complications after the removal of impacted mandibular third molars. Types of Studies Reviewed The authors searched for randomized clinical trials in which the investigators evaluated the efficacy of LLLT compared with that of placebo or no treatment. Two reviewers independently screened studies, extracted data, and assessed risk of bias. The authors used random effects model meta-analysis and the Grading of Recommendations Assessment, Development and Evaluation approach to rate the certainty of evidence. Results The authors included 21 studies. There was low-certainty evidence that LLLT results in less pain at 2 days after surgery (mean difference [MD], −1.42 on a 10 point scale; 95% confidence interval [CI], −2.18 to −0.67) and moderate certainty that it results in negligibly less pain at 7 days (MD, −0.59; 95% CI, −0.96 to −0.22); moderate-certainty evidence that LLLT has a negligible benefit on reducing trismus at 2 days (MD, −3.42 millimeters; 95% CI, −5.34 to −1.50) and at 7 days after surgery (MD, −2.30 mm; 95% CI, −3.96 to −0.64); lastly, there was moderate-certainty evidence that LLLT results in less postoperative swelling at 2 days (standardized MD, −0.82; 95% CI, −1.28 to −0.35) and low-certainty evidence that LLLT results in negligibly less postoperative swelling at 7 days after surgery (standardized MD, −0.17; 95% CI, −0.4 to 0.07). Low-quality evidence suggests that LLLT will not cause adverse effects. Conclusions and Practical Implications LLLT probably has negligible benefits but may not result in adverse events. Evidence does not support the use of LLLT in clinical practice to reduce complications after impacted mandibular third-molar surgical extractions.