Is Intracanal Cryotherapy Effective in Reducing Postoperative Endodontic Pain? An Updated Systematic Review and Meta-Analysis of Randomized Clinical Trials

This research aimed to assess the potency of intracanal cold therapy in diminishing postoperative endodontic pain. PubMed, Scopus, the Cochrane Library, EMBASE, the Web of Science, grey literature, and endodontic journals were used to identify randomized controlled clinical trials evaluating postoperative pain after a final irrigation with a cold irrigant (as an experimental group) and a room temperature irrigant (as a control group). The risk of bias was rated according to the Cochrane Collaboration’s tool and the Grading Recommendation Assessment, Development, and Evaluation (GRADE) system was used to estimate the evidence quality. For the meta-analysis, a random effects model was utilized. The qualitative analysis contained 16 studies and the quantitative analysis contained 9 studies. The experimental groups showed a reduction in postoperative pain at 6 h (mean difference (MD) = −1.11; p = 0.0004; I2 = 72%; low quality evidence), 24 h (MD = −1.08; p = 0.003; I2 = 92%; low quality evidence), 48 h (MD = −0.38; p = 0.04; I2 = 81%; low quality evidence), and 72 h (MD = −0.69; p = 0.04; I2 = 90%; low quality evidence). A higher quality of evidence from more clinical trials is needed.


Introduction
One of the essential parts of endodontic therapy is to prevent and manage postendodontic pain [1]. The prevalence of postoperative pain after endodontic treatment ranges between 3 and 58% [2]. The reported frequency of teeth that showed persistent pain at 6 months or more after root canal treatment varied from 4.9-12% [3][4][5][6][7]. Moreover, the prevalence and severity of pain were not shown to differ significantly among the number of root canal treatment visits [8]. Postoperative pain following endodontic treatment is due to chemical, mechanical, or microbial injury to the periradicular tissue [9]. Several techniques and treatments have been described in the literature to control postoperative pain in endodontics including the prescription of medication [10][11][12], the use of intracanal therapies [13][14][15], and occlusal reduction [16]. Nevertheless, each technique and treatment has its own disadvantages. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been documented to have harmful effects on several body systems such as the gastric mucosa and hepatic system [17]. Furthermore, the initial exposure to opioids might lead to respiratory depression, nausea, and the risk of long-term use, abuse, and overdose [18]. The use of intracanal therapies (such as calcium hydroxide, laser application, and analgesic solutions) and occlusal reduction have contradictory effects on reducing postoperative endodontic pain in the literature [19,20]. Cryotherapy involves reducing the tissue temperature for curative purposes [21]. It was first used by the ancient Egyptians circa 3000 BCE to cure injuries and decrease inflammation [22]. Since 1960, it has been used in medicine to relieve the pain of sports injuries [23]. Its mechanism of action in reducing pain involves decreasing the tissue temperature and reducing the flow of blood and metabolic activity [24]. In dental practice, study design, the pulpal and periapical diagnosis, the age range of participants, the type of teeth, preoperative pain in the experimental and control groups, the postoperative drug prescription, the pain evaluation scale utilized, the total sample size, the irrigation methods utilized, the type and concentration of irrigant utilized, the irrigant activation, and postoperative pain one day minimum after the procedure, the results, and the conclusion. The risk of bias was rated according to Cochrane Collaboration's tool for assessing the risk of bias in randomized trials (RoB 2) [65]. For the meta-analysis, RevMan software (version 5.4; The Cochrane Collaboration, London, UK) was used. To indicate the effect estimate, the mean differences (MDs) with 95% confidence intervals (CIs) and a random effects model were used. The I 2 index was used to test the heterogeneity. The quality of evidence was judged using the GRADE system (www.GradeWorking-Group.org, accessed on the 1 September 2021) [66].

Postoperative Pain at 6 h
Six studies (n = 450) revealed postoperative pain at 6 h [45,48,49,53,54,57]. A metaanalysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (mean difference (MD) = −1.11; 95% confidence interval (CI) = −1.72 to −0.5; p = 0.0004; I 2 = 72%) (Figure 3). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table 2). iron. Res. Public Health 2021, 18, x 10 of 18 Figure 2. Summary of the risk assessment bias (RoB 2) of the included randomized controlled trials.

Postoperative Pain at 6 h
Six studies (n = 450) revealed postoperative pain at 6 h [45,48,49,53,54,57]. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (mean difference (MD) = −1.11; 95% confidence interval (CI) = −1.72 to −0.5; p = 0.0004; I 2 = 72%) (Figure 3). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table 2).     * CI: Confidence interval; § GRADE (Grading of Recommendations, Assessment, Development and Evaluation) certainty ratings: very low certainty: the authors have very little confidence in the effect estimate (the true effect is probably markedly different from the estimated effect); low certainty: the authors have little confidence in the effect estimate (the true effect might be markedly different from the estimated effect); moderate certainty: the authors have moderate confidence in the effect estimate (the authors believe that the true effect is probably close to the estimated effect); high certainty: the authors have a lot of confidence that the true effect is similar to the estimated effect; a concerns of a risk of bias; b substantial heterogeneity; c direct comparison; d narrow confidence interval.

Postoperative Pain at 24 h
Nine studies (n = 763) revealed postoperative pain at 24 h [45,46,48,49,51,53,54,57,58]. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −1.08; 95% CI = −1.79 to −0.38; p = 0.003; I 2 = 92%) (Figure 4). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" (

Postoperative Pain at 48 h
Five studies (n = 440) revealed postoperative pain at 48 h [45,49,51,57,58]. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −0.38; 95% CI = −0.73 to −0.02; p = 0.04; I 2 = 81%) ( Figure 5). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table  2).

Postoperative Pain at 48 h
Five studies (n = 440) revealed postoperative pain at 48 h [45,49,51,57,58]. A metaanalysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −0.38; 95% CI = −0.73 to −0.02; p = 0.04; I 2 = 81%) ( Figure 5). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" (Table 2).

Postoperative Pain at 48 h
Five studies (n = 440) revealed postoperative pain at 48 h [45,49,51,57,58]. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −0.38; 95% CI = −0.73 to −0.02; p = 0.04; I 2 = 81%) ( Figure 5). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table  2).

Postoperative Pain at 72 h
Five studies (n = 563) revealed postoperative pain at 72 h [46,48,51,53,58]. However, one study had zero scores for the mean and standard deviation for the intracanal cold therapy group (experimental group) [53]; therefore, the MD and CI were not estimable and they were not included in the statistics. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −0.69; 95% CI = −1.34 to −0.05; p = 0.04; I 2 = 90%) ( Figure 6). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table 2).

Postoperative Pain at 72 h
Five studies (n = 563) revealed postoperative pain at 72 h [46,48,51,53,58]. However, one study had zero scores for the mean and standard deviation for the intracanal cold therapy group (experimental group) [53]; therefore, the MD and CI were not estimable and they were not included in the statistics. A meta-analysis demonstrated a significant statistical diminution in postoperative pain in the intracanal cold therapy group (experimental group) compared with the room temperature irrigant group (control group) (MD = −0.69; 95% CI = −1.34 to −0.05; p = 0.04; I 2 = 90%) ( Figure 6). The GRADE was low because of concerns with the RoB 2 and the substantial heterogeneity, which indicated that "we have little confidence in the effect estimate and the true effect might be markedly different from the estimated effect" ( Table 2).

Postoperative Pain at 7 Days
Three studies (n = 113) revealed postoperative pain at seven days [46,57,58]. Two of these studies [57,58] had zero scores for the mean and standard deviation for the experimental group. Therefore, the MD and CI were not estimable.

Discussion
The present systematic review and meta-analysis showed that the application of intracanal cryotherapy minimized endodontic pain at 6, 24, 48, and 72 h postoperatively. These results were consistent with previous systematic reviews [59,60]. However, Monteiro et al. in their systematic review and meta-analysis showed that pain was only minimized 6 and 24 h postoperatively [61]. After seven days, there was a reduction in the postoperative pain scores in the intracanal cryotherapy group (experimental group) compared with the room temperature group (control group) but this reduction could not be proven statistically due to inestimable MD and CI values. Our results were in contrast with those reported by Gupta et al. in their systematic review and meta-analysis where they showed that intracanal cryotherapy did not play a significant role in minimizing postendodontic pain [62]. Pain reduction after cryotherapy application is due to several mechanisms including changes in the nerve conduction velocity, inhibition of

Postoperative Pain at 7 Days
Three studies (n = 113) revealed postoperative pain at seven days [46,57,58]. Two of these studies [57,58] had zero scores for the mean and standard deviation for the experimental group. Therefore, the MD and CI were not estimable.

Discussion
The present systematic review and meta-analysis showed that the application of intracanal cryotherapy minimized endodontic pain at 6, 24, 48, and 72 h postoperatively. These results were consistent with previous systematic reviews [59,60]. However, Monteiro et al. in their systematic review and meta-analysis showed that pain was only minimized 6 and 24 h postoperatively [61]. After seven days, there was a reduction in the postoperative pain scores in the intracanal cryotherapy group (experimental group) compared with the room temperature group (control group) but this reduction could not be proven statistically due to inestimable MD and CI values. Our results were in contrast with those reported by Gupta et al. in their systematic review and meta-analysis where they showed that intracanal cryotherapy did not play a significant role in minimizing postendodontic pain [62]. Pain reduction after cryotherapy application is due to several mechanisms including changes in the nerve conduction velocity, inhibition of nociceptors, and a reduction in the metabolic enzyme activity level [67][68][69]. It has been reported that at a 7 • C body temperature, myelinated A-δ fibers are completely deactivated; nonmyelinated C-fibers are deactivated at 3 • C [70,71]. Moreover, Vera et al. in their in vitro study concluded that finalizing the irrigation with a 2.5 • C saline solution decreased the temperature of the external root surface by more than 10 • C for a 4 min period. This decrease in temperature is sufficient to decelerate the inflammatory reaction and reduce the induction of pain-producing substances, leading to local anti-inflammatory effects in the periradicular tissues [36]. Eight of the thirteen studies that compared the use of analgesics between the intracanal cold therapy and the control groups postoperatively showed that fewer patients used analgesics in the intracanal cold therapy group than in the control group. A previous systematic review analyzed the effect of cold therapy on pain reduction and analgesic use after a total knee arthroplasty. Very low certainty evidence was found that cold therapy decreased analgesic use and no evidence showed that it reduced pain [72]. On the other hand, Watkins et al. concluded that cryotherapy decreases postoperative pain and the use of analgesics by patients undergoing major abdominal operations [24].
Our included studies had different numbers of treatment visits to perform root canal treatment; nine studies mentioned that root canal treatment was completed in one visit [43,44,46,[49][50][51][52][53]57], six studies performed root canal treatment in two visits [45,47,48,[54][55][56], and one study did not mention any information about the number of root canal treatment visits [58]. However, all of them showed a reduction in postoperative pain compared with preoperative pain. This is consistent with a previous systematic review that evaluated the predictors of postoperative endodontic pain and concluded that the number of treatment visits had no significant effect on postoperative pain [73]. On the other hand, Izadpanah et al. in their systematic review and meta-analysis concluded that single-visit root canal therapy has a higher risk of postoperative pain than multiple visits with acceptable statistical heterogeneity and a moderate quality of the studies [74].
The temperature of the final cold irrigant ranged from 1.5 • C to 4 • C for 1 to 5 min among the included studies. The optimal temperature application duration of intracanal cold therapy has not been concluded as none of the studies compared the durations; however, a continuous exposure to a low temperature below −20 • C leads to cell death and tissue destruction [75,76] and intermittent applications of cryotherapy can enhance its therapeutic effect in relieving pain after an acute soft tissue injury [77].
An EndoVac negative pressure irrigation system was used along with needle syringe activation in five studies [43,44,48,51,57]. A previous systematic review analyzed the effect of using an EndoVac versus a needle syringe in controlling postoperative pain; no statistically significant difference was found [60]. On the other hand, it was shown that an EndoVac might cause less postoperative pain due to less apical extrusion of debris [78].
To the best of our knowledge, this is the first systematic review that determined the effect of intracanal cold therapy on postoperative endodontic pain by utilizing the second version of the Cochrane risk of bias tool for randomized trials (RoB 2). The Cochrane risk of bias tool 2 (RoB 2) is designed to focus on the results, leading to a better quality of the risk of bias assessments. Furthermore, the RoB 2 has an approach that applies a granular structure of knowledge by indicating questions and a wider range of possible answers that guide the review authors to focus on the context of clinical trials [79].
In our systematic review, a few concerns of bias arose from the randomization process due to a lack of information about the randomization and the concealment of the allocation process [45,46,49,50,54,57]. A bias associated with inadequate allocation concealment may cause an exaggeration of the estimated treatment effect and affect the meta-analysis results [80]. A bias due to deviations from the intended intervention was observed in eight studies where the people delivering the interventions were not blinded and no information was provided regarding the blinding of the participants [43,[45][46][47]50,51,54,57]. A previous study found that the risk of bias in blinding the participants and personnel in endodontics clinical trials is the highest and will lead to an overestimation of the results [81]. Missing outcome data were not clear in two studies [47,50], which might lead to doubts regarding the estimate of the effect [82]. The outcome of postoperative pain was assessed by the patients themselves and no information was provided regarding the awareness of the outcome assessors of the intervention they received in five studies [45,50,54,55,57]. That might lead to bias in the outcome measurement. A bias in the selection of the reported result was found in three studies [50,54,57], which might cause misleading results. These biases might explain the significant reduction in postoperative endodontic pain at 6, 24, 48, and 72 h that was found in the meta-analysis.
The GRADE was utilized to rate the certainty of evidence and it was found to be low due to serious concerns about the risk of bias and inconsistency. These results were in contrast to a previous systematic review that also evaluated the efficacy of intracanal cold therapy for the management of postoperative endodontic pain and the certainty of evidence was judged as moderate [60]. Another systematic review evaluated the same topic but the certainty of evidence was considered very low due to serious concerns with the risk of bias and inconsistency as well as very serious concerns with the imprecision [61].
This systematic review has a few limitations including the variability among the included studies in the study design, the diagnosis of pulpal and periapical areas, the type of teeth included in each study, the preoperative pain status, the experimental group irrigation protocol, the sample size, and the number of treatment visits. These variations among the included studies might affect the intervention effects.
Although intracanal cryotherapy is a simple and inexpensive method that might reduce postoperative endodontic pain, the certainty of evidence illustrated in this research was low. This signifies the need for well-designed trials with precise parameters and variable controls to establish its effective and definitive use in endodontic clinical practice.

Conclusions
Within the limitations of this study, the application of intracanal cold irrigation showed low certainty of evidence in reducing postoperative endodontic pain. Additional better designed clinical trials are required to establish the effective use of intracanal cryotherapy in controlling postoperative endodontic pain in clinical practice.