Dexamethasone Increases the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis

Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration’s risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel–Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo (n = 502; p < 0.001; OR = 2.59; 95% CIs: 1.46 to 4.59). Moreover, patients who were given dexamethasone had lower pain scores at 6 h (n = 302; p < 0.001; MD= −1.43; 95% CIs: −2.28 to −0.58), 12 h (n = 302; p < 0.0001; MD = −1.65; 95% CIs: −2.39 to −0.92), and 24 h (n = 302; p < 0.0008; MD = −1.27; 95% CIs: −2.01 to −0.53) when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.


Introduction
In the field of endodontics, symptomatic irreversible pulpitis (SIP) is a dental emergency with moderate-to-severe pain upon thermal stimulus [1][2][3][4]. In this regard, approximately 80% of patients with SIP present dental anesthesia failures after a root canal treatment [1,3,4]. The reasons that this condition makes dental anesthesia difficult are not fully known [4]. Nevertheless, the possible causes of the anesthetic failure in patients with SIP are related to the inflammatory processes-altered Na + channel expression in atypical sites when compared to normal pulps [5], altered membrane potentials, and decreased excitability thresholds [6]-of the pulp [4].
Some clinical assays have been carried out to determine the effect of dexamethasone on the success of dental anesthesia in patients with SIP, and interesting results have been found [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The main aim of this systematic review and meta-analytical assessment was to evaluate the effects of the systemic and local administration of dexamethasone on the anesthetic success rate, pain intensity, and adverse effects in patients with SIP.

Registration
This systematic review was developed in strict adherence to the guidelines for reporting systematic reviews and meta-analyses of studies that assess health care interventions (PRISMA) [25][26][27]. The protocol was registered in PROSPERO: CRD42021279262.

Focused Question
Our research team posed the following question: How effective is dexamethasone compared to a placebo or a local anesthetic in terms of anesthetic success rate and postendodontic pain management in patients with SIP? Control: A group using placebo/a group with local anesthesia. Outcomes: Anesthetic success rate, anesthesia depth and duration, pain intensity using the visual analog scale (VAS), pain intensity evaluated through the Heft-Parker VAS, rescue analgesic medication, and adverse effects.
These criteria were written according to the PICO recommendations [28].

Exclusion Criteria
Clinical studies reporting a loss to follow-up of more than 20%. High risk of bias according to the Cochrane Collaboration's risk-of-bias tool.

Information Search
The keywords used to perform PubMed and Google Scholar searches were "dexamethasone", "corticosteroids", "glucocorticoids", "symptomatic irreversible pulpitis", "active dental pain", and "dental pain". At least two keywords were used for the identification of articles, i.e., "dexamethasone" AND "symptomatic irreversible pulpitis". In addition, three filters were employed in PubMed: article type (journal article, clinical trial, clinical study, or randomized controlled trial), language (English or Spanish), and species (humans). The retrieved articles were saved for further assessment. Articles published up to 1 November 2021 were eligible.

Risk of Bias Assessment
The Cochrane Collaboration's risk-of-bias tool was employed [29][30][31]. Each of the 7 points of the tool rates the risk of bias as low-risk (green), medium-risk (yellow), or high-risk (red). Only those studies that obtained low and moderate risk-of-bias scores were considered for the qualitative and quantitative analyses [29][30][31]. Article ID data, design, treatments, sample size, dose, anesthetic success rate, anesthesia depth and duration, thermal or electric pulpal tests, pain intensity, rescue analgesic  medication, and adverse effects were obtained. Yavari et al. 2019 [23] reported two dexamethasone groups. Considering that both dexamethasone groups were included in the pain intensity evaluation by the VAS, the sample size of the control group was divided in half in the pooled analysis. Data of normal dexamethasone group versus the control group were designed in the meta-analysis as "a" (Yavari et al. 2019a), and long-lasting dexamethasone in comparison with the control group was included as "b" (Yavari et al. 2019b).

Information Extraction
Two independent assessors carried out the bias assessment and data extraction. Any disagreements between them were reviewed and decided by a third evaluator, when necessary.

Statistical Analysis
The Review Manager 5.3 software for Windows was used for data analysis, forest plots, and funnel plots. All meta-analyses were conducted using the random-effects model. The anesthetic success was analyzed using the Mantel-Haenszel test and odds ratios (ORs). On the other hand, pain intensity was assessed with the inverse variance and standardized mean difference. The data heterogeneity was measured with the I 2 test. Funnel plots were used to represent the publication bias of the included clinical trials. The influence of the weight of each study on the results of the meta-analysis was evaluated through a sensitivity study. A p-value of ≤0.05 and odds ratio or a mean difference ≥ 1 (a positive or negative value on a two-sided test) within a 95% confidence interval was considered to be a statistically significant difference [29,30,[32][33][34][35].
ASA I or II patients with pain in a lower molar (moderate-to-severe pain) and diagnosis of SIP with a normal periapical radiograph. Patients with prolonged positive response to cold tests. For all patients, IANB was performed using lidocaine 2%, and 1:200,000 epinephrine was employed. The anesthetic success index and the heart rates were assessed.
Intraligamentary dexamethasone administration increased the success rate of anesthesia.
Healthy patients aged 18 to 65 years with a diagnosis of SIP (moderate-to-severe pain) in a mandibular molar, radiographically normal periapical area, and no pain on percussion were included. Patients without analgesic medication, at least 12 h before the study. Patients with prolonged positive response to cold tests. All patients were administered an IANB using 4% articaine with 1:200,000 epinephrine. Postoperative pain intensity, rescue analgesic medication, and adverse effects were evaluated.
Dexamethasone was more effective for pain control when compared with saline.
Healthy patients aged 18 to 65 years with a diagnosis of SIP (moderate-to-severe pain) in a mandibular molar, radiographically normal periapical area, and no pain on percussion were included. Patients without analgesic medication, at least 24 h before the study. Patients with prolonged positive response to cold tests. All patients were given an IANB using 4% articaine with 1:200,000 epinephrine. Anesthesia was successful when the pain level of patients included no pain or mild pain. Sensory blockade, duration of anesthesia, success index, and adverse effects were assessed.

Dexamethasone
increased the duration of anesthetic activity when compared with saline. A similar anesthesia rate for dexamethasone and placebo was reported. Group C: placebo (n = 25). All treatments were administered using the oral route.
Emergency patients diagnosed with SIP of a mandibular posterior tooth. IANB was performed. However, the anesthetic agent used was not disclosed. The anesthesia success was analyzed.
Healthy individuals aged 20 to 50 years and presenting a diagnosis of symptomatic and asymptomatic irreversible pulpitis with a normal periapical condition. Ibuprofen 1.6 g was used during the two previous days. Patients with prolonged positive response to cold tests. For all subjects, the IANB was performed using lidocaine and 1:100,000 epinephrine. Post-treatment pain was evaluated with the VAS.
Both dexamethasone groups had better postoperative pain relief than saline.
The pain control assessment was performed with six clinical assays. All of these clinical trials found that dexamethasone was more effective than placebo in patients with SIP [10,15,18,19,22,23].

Quantitative Evaluation
The local assessment of the anesthetic success rate of dexamethasone and placebo was performed using four clinical studies (n = 249) [8,9,11,16]. Local dexamethasone and local placebo had similar anesthetic success rates (p < 0.08, Figure 3). Moreover, the systemic administration of dexamethasone versus systemic placebo was performed using four clinical investigations (n = 253) [14,17,20,21]. The systemic administration of dexamethasone showed a superior anesthetic success rate in comparison with placebo (n = 253, p < 0.003, Figure 3). Likewise, global evaluation of the anesthetic success rate was performed using data from eight clinical studies (n = 502). The overall anesthetic success rate of dexamethasone was 60.55%, while that of saline was 38.64% [8,9,11,14,16,17,20,21]. The pooled analysis shows a statistical difference in favor of dexamethasone when compared to placebo (p < 0.001, Figure 3).
Moreover, no study reported that dexamethasone improved the depth of anesthesia, whereas one dexamethasone clinical trial [11] found an increased duration of anesthesia.
The pooled evaluation of pain intensity was carried out using the data of three clinical trials (n = 302) [15,22,23]. The pre-endodontic pain scores were similar between the dexamethasone group and the control group. In this sense, patients who received dexamethasone had lower pain intensity at 6 (p < 0.001), 12 (p < 0.0001), and 24 (p < 0.0008) postoperative hours when compared to those who were given local anesthetics (Figure 4).  The number of patients who took rescue analgesics in the dexamethasone group was lower in comparison with controls, but a statistical difference was not found (n = 58) [10,18]. On the other hand, the risk of adverse reactions was determined with data from five clinical assays (n = 436) [9,11,14,20,22]. Only one patient in the dexamethasone group and no patients in the control group presented adverse effects. The number of patients who took rescue analgesics in the dexamethasone group was lower in comparison with controls, but a statistical difference was not found (n = 58) [10,18]. On the other hand, the risk of adverse reactions was determined with data from five clinical assays (n = 436) [9,11,14,20,22]. Only one patient in the dexamethasone group and no patients in the control group presented adverse effects.

The Sensitivity Evaluation and Publication Bias
The sensitivity analysis did not show important changes in the results of either the anesthetic success index or the pain intensity meta-analyses. Moreover, the visual evaluation identified no publication bias using a funnel plot ( Figure 5).  [8,9,11,14,16,17,20,21].

Discussion
The most important finding of this systematic review and meta-analysis is that systemic-but not local-administration of dexamethasone increased the anesthetic success rate when compared to systemic placebo in patients with SIP. However, the data trend shows a positive effect in favor of the local administration of dexamethasone, for which it is likely that increasing the sample size could achieve this statistical difference. Moreover, dexamethasone produced lower pain intensity scores at 6, 12, and 24 h when compared to the control group. On the other hand, the evaluation of depth and duration of anesthesia, along with the adverse effects of dexamethasone, was not possible, due to the small number of studies reporting these clinical data. No study reported an increase in anesthetic depth, while only one trial reported that dexamethasone prolonged the duration of anesthesia. Aksoy et al. [11] demonstrated that submucosal dexamethasone (349.33 ± 28.24 min) increased the anesthetic effects of IANB using 4% articaine with 1:200000 epinephrine when compared with saline (271.80 ± 17.10 min) [11]. In this context, Pehora et al. [36] carried out a systematic review and meta-analysis, and their findings showed a prolongation of the sensory block when dexamethasone was employed as an adjuvant across a perineural or intravenous route for the peripheral nerve block in upper-limb surgery. Moreover, the local use of the drug could have some advantages in comparison to the systemic administration; for example, the drug is administered exactly where it should exert its therapeutic effect, increasing its concentration and minimizing the time it takes to get to the site where it is needed [37][38][39][40][41][42][43][44].
The Cochrane Collaboration's risk-of-bias tool showed that all items had a general result indicating a low risk of bias. The items with the highest risk of bias were blinding of patients and medical personnel (performance bias), and blinding of outcome assessment (detection bias) ( Figure 2). Moreover, the evaluation of the publication bias of the local administration of dexamethasone showed a slight tendency to publish articles that Figure 5. The publication bias [8,9,11,14,16,17,20,21].

Discussion
The most important finding of this systematic review and meta-analysis is that systemic-but not local-administration of dexamethasone increased the anesthetic success rate when compared to systemic placebo in patients with SIP. However, the data trend shows a positive effect in favor of the local administration of dexamethasone, for which it is likely that increasing the sample size could achieve this statistical difference. Moreover, dexamethasone produced lower pain intensity scores at 6, 12, and 24 h when compared to the control group. On the other hand, the evaluation of depth and duration of anesthesia, along with the adverse effects of dexamethasone, was not possible, due to the small number of studies reporting these clinical data. No study reported an increase in anesthetic depth, while only one trial reported that dexamethasone prolonged the duration of anesthesia. Aksoy et al. [11] demonstrated that submucosal dexamethasone (349.33 ± 28.24 min) increased the anesthetic effects of IANB using 4% articaine with 1:200000 epinephrine when compared with saline (271.80 ± 17.10 min) [11]. In this context, Pehora et al. [36] carried out a systematic review and meta-analysis, and their findings showed a prolongation of the sensory block when dexamethasone was employed as an adjuvant across a perineural or intravenous route for the peripheral nerve block in upper-limb surgery. Moreover, the local use of the drug could have some advantages in comparison to the systemic administration; for example, the drug is administered exactly where it should exert its therapeutic effect, increasing its concentration and minimizing the time it takes to get to the site where it is needed [37][38][39][40][41][42][43][44].
The Cochrane Collaboration's risk-of-bias tool showed that all items had a general result indicating a low risk of bias. The items with the highest risk of bias were blinding of patients and medical personnel (performance bias), and blinding of outcome assessment (detection bias) ( Figure 2). Moreover, the evaluation of the publication bias of the local administration of dexamethasone showed a slight tendency to publish articles that report an effect in favor of this drug when administered as an adjunct to dental anesthesia in patients with SIP, whereas reports on the systemic administration of dexamethasone showed that published scientific articles present negative results-that is, dexamethasone has no effect on dental anesthesia in patients with SIP.
Waldron et al. [45] carried out a systematic review and meta-analysis to evaluate the analgesic efficacy of dexamethasone and placebo in patients undergoing general anesthesia. They found better postoperative pain control in patients who received dexamethasone in comparison to those who were given placebo [45]. Knezevic et al. [46] evaluated the effect of perineural dexamethasone added to local anesthesia. The authors reported that dexamethasone reduced postoperative pain when added to the brachial plexus block. However, it increased the anesthesia latency and the duration of the motor block [46]. Nogueira et al. [7] performed a systematic review and meta-analytical assessment of the analgesic efficacy of systemic administration of dexamethasone in patients with SIP. The authors found that systemic administration of dexamethasone was more effective than placebo at 8, 12, and 24 h for pain control in patients with SIP. However, Nogueira et al. [7] did not evaluate the anesthetic success or the adverse effects. Our meta-analysis reports, for the first time, the positive effect of the systemic administration of dexamethasone on the anesthetic success index in patients with SIP.
Some studies have been carried out to determine the adverse effects of dexamethasone in humans. Polderman et al. [47] reported that dexamethasone slightly increases glucose levels, but not the infection risk or wound healing. Moreover, the multi-dose administration of dexamethasone could affect different organs and/or systems, such as the nervous, musculoskeletal, cardiovascular, digestive, endocrine, and renal systems [48]. In this study, dexamethasone was used as a single dose, and the data showed only one clinical trial (one patient in the dexamethasone group) reporting adverse effects. For this reason, pooled analysis was not performed.
The main advantages of this study include an adequate methodology, rigorous and conservative statistical methods, and the available evidence with a lower risk of bias to perform a powerful pooled analysis [29,30,[32][33][34][35]49]. Local administration of dexamethasone was performed via the submucosal, supraperiosteal, or intraligamentary routes, and different doses of dexamethasone were used. Therefore, both the routes and the doses could be considered limitations of this study. It is important to note that the results of the local and systemic application of dexamethasone were similar.

Conclusions
In conclusion, this is the first systematic review and meta-analysis showing that the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.