Efficacy of Preemptive Dexamethasone versus Methylprednisolone in the Management of Postoperative Discomfort and Pain after Mandibular Third Molar Surgery: A Systematic Review and Meta-Analysis

The corticosteroids have been used for preemptive management of surgical sequelae after mandibular third molar extraction. The aim of this article was to review the efficacy of methylprednisolone versus dexamethasone in the management of postsurgical pain, swelling, and trismus after mandibular third molar surgery. Randomized, double-blinded studies from PubMed, CINAHL, Scopus, DOSS, Cochrane central, and Web of Science were identified by using a search strategy. Randomized controlled trials evaluating the efficacy of use of dexamethasone versus methylprednisolone for mandibular third molar extraction were only considered. The studies involving the use of any other corticosteroid agent were excluded. Outcomes assessed were postoperative pain, the number of rescue analgesics required, swelling, trismus, and adverse events. The search strategy yielded 1046 articles for title and abstract screening, out of which only seven studies were included in the systematic review after full text screening. There was considerable heterogeneity between the studies with regards to the method as well as the parameters assessed. Risk of bias was low in three studies and unclear in other four studies. On pooled analyses, there was no significant difference with respect to pain, rescue analgesics, and swelling in the test and the control group. Forest plot analysis showed that dexamethasone had lesser trismus in early postoperative period (postoperative day 2) as compared to methylprednisolone. None of the included studies reported any adverse effects. Both the corticosteroids have similar efficacy in reducing the postoperative pain and swelling; however, dexamethasone showed statistically significant difference from methylprednisolone in reducing trismus (estimated standardized mean difference of −0.69 mm; 95% CI: −1.01 to −0.38; p < 0.0001) in the early postoperative period. However, due to statistical heterogeneity, quality of the evidence for the review was low to moderate. Hence, more studies with larger study sample and low risk of bias are needed to confirm these results.


Introduction
Transalveolar extraction of an impacted mandibular third molar (M3M) is a routine minor oral surgical procedure. It results in an acute and overt infammatory response that might lead to postoperative complications such as pain, trismus, and edema [1,2]. Trismus can lead to functional limitations and edema causing signifcant esthetic concerns; both of them can potentially afect oral health-related quality of life [3]. Although the efect is for a few days, it is generally unacceptable to the patient and further dissuades them from seeking appropriate treatment. Hence, maxillofacial surgeons attempt to minimize the postoperative sequelae after M3M surgical extraction.
Modifcation of fap design, atraumatic osteotomy, cryotherapy, and pharmacological agents (corticosteroids) have been tried previously to reduce early postoperative complications [3]. Many maxillofacial surgeons choose a single dose of preemptive corticosteroid during the surgical extraction of M3M. Te potent anti-infammatory action inhibits vasodilatation and decreases cellular exudates and fbrin deposits. Te suppression of the vasoactive substances' (prostaglandins and leukotrienes) production reduces the edema [4]. Although the anti-infammatory action of corticosteroids is well-established, their role in reducing postoperative complications remains inconclusive [5,6]. Te potential adverse efects of the steroids are delayed wound healing and increased risk of infection, usually seen only with prolonged use of corticosteroids. Te use of single-dose preemptive corticosteroids has not shown adverse efects [4,7].
Te two most preferred corticosteroids in minor oral surgery are methylprednisolone and dexamethasone. Tey predominantly exert glucocorticoid action and have minimal efect on sodium retention or mineralocorticoid action. Methylprednisolone is an intermediate-acting corticosteroid with 4-5 times more potency than hydrocortisone. Dexamethasone is a long-acting corticosteroid with 40-50 times more potency than hydrocortisone [8].
A previous systematic review included 28 randomizedcontrolled trials (RCTs) evaluating the use of corticosteroids in M3M surgery. It was reported that the use of corticosteroids had a signifcant reduction in postoperative trismus and infammation. However, there was no consensus regarding the preferred corticosteroid, route, and dosage [9]. A systematic review compared the efcacy of dexamethasone versus methylprednisolone in M3M surgeries, which included RCTs that used the submucosal corticosteroid [10]. With this background, this systematic review evaluated the efcacy of dexamethasone versus methylprednisolone in managing postoperative discomfort and pain after M3M surgery.

Protocol.
Tis systematic review was reported as per the "PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)" guidelines [11]. Te protocol was registered with the PROSPERO (CRD42020161341). . Te PICO acronym  was used to defne the research question. Te search was  conducted for studies on healthy volunteers or asymptomatic patients needing surgical extraction of impacted  M3M under local anesthesia. Te intervention under study  was the administration of preemptive methylprednisolone, which was compared with preemptive dexamethasone. Te outcome measures were the postoperative pain assessment using a visual analogue scale (VAS), the number of rescue analgesics consumed, trismus, and edema. Studies of the efect of any other corticosteroid agents and studies conducted for any other surgical procedure other than removal of impacted M3M were excluded.

Inclusion and Exclusion Criteria
Trismus assessment is conducted by measuring the change in the maximal interincisal distance (MID) or maximal interincisal opening (MIO) from the preoperative value to the subsequent measurements at follow-up visits after tooth extraction [12]. Postextraction facial swelling assessment described by Ustun et al. involved measurement of three lines, i.e., line joining outer canthus to gonion, tragus to commissure line, and tragus to soft tissue pogonion line [13]. Another method for assessing facial swelling is measuring the "tragus-commissure line", "gonioncommissure line", and "gonion-external canthus line" [14]. Alternatively, a 2-line measurement involving gonionexternal canthus line and tragus-commissure line has also been described to evaluate facial swelling [15].
Randomized controlled trials published without publication date or language restrictions were included. Te laboratory studies, abstracts, case series, review articles, editorials, interviews, discussions, and opinions were excluded.

Search Strategy.
Six electronic databases were searched using a combination of terms from inception to June 30, 2022 (Table 1 and Figure 1). In addition, a grey literature search revealed three articles. Also, the references in the included studies were hand searched. Te search was carried out using a combination of terms: dexamethasone, methylprednisolone, and M3M (Table 1).

Data Extraction and Management.
Two review authors (A.S. and P.K.C.) performed title, abstract, and full-text screening. Two review authors (A.S. and S.G.) independently performed the data extraction. Information extracted was author names, year, sample sizes, mean age, gender distribution, difculty index, type, dose, and route of corticosteroid administration, and the outcome results such as pain scores, rescue analgesics, swelling, trismus, and complications, if any. Conficts were resolved after a discussion with the third review author (P.K.C.). A third reviewer (K.S.) resolved conficts.

Assessment of Risk of Bias in RCTs.
Te risk of bias was assessed by the tool described in the "Cochrane Handbook for Systematic Reviews of Interventions" [16]. Two independent reviewers (A.S. and S.G.) assessed the risk of bias for the included studies. A third reviewer (P.K.C.) resolved disagreements.

Statistical
Analyses. Data analysis was performed using "Review Manager (RevMan)" (Computer program), ver. 5.4.1 (Te Cochrane Collaboration, 2020). Te heterogeneity of studies was assessed using the I 2 statistic and χ 2 . We used the standardized mean diference and random efects model to generate the forest plot.

Search Results.
Six electronic databases PubMed (n � 884), CINAHL (n � 6), Scopus (n � 22), DOSS (n � 71), Cochrane central (n � 12), and Web of Science (n � 48) yielded a total of 1046 articles. After removing duplicated records (203), during abstract and title screening, 815 articles were excluded, and 27 articles were taken up for full-text analysis. Out of 27 articles, permission for 1 article was not obtained, and another article was excluded as it lacked comprehensible data. [15] Finally, seven studies were included for the qualitative and quantitative synthesis (metaanalysis) (Figure 1).

Bias Assessment.
Seven studies met the selection criteria according to the "Cochrane collaboration's risk of bias tool" ( Table 2). None of the included studies had a low risk of bias across all domains. However, none of the studies had a high risk of bias.

Qualitative Evaluation.
Six studies used a preoperative approach [14,[17][18][19][20][21], while the time of steroid administration was not specifed in one study [22]. Five studies were conducted on a split-mouth randomized controlled trial design [14,[17][18][19]22]. Only one study [17] used diferent  Te Scientifc World Journal routes of corticosteroid administration, i.e., intravenous administration of methylprednisolone and intramasseteric dexamethasone, while the rest of the studies had similar methods of administration in both methylprednisolone and dexamethasone groups. Two studies used the intramasseteric approach [17,22], two studies used the submucosal approach [20,21], and two studies used the oral method of administration of corticosteroids [18,19]. Six studies used a similar dose of methylprednisolone, i.e., 40 mg; one study [14] used a variable dose of methylprednisolone, i.e., 1.5 mg/kg body weight. Four studies used a 4 mg dose of dexamethasone [14,17,21], whereas the other four used an 8 mg dose of dexamethasone [18][19][20]22]. Two studies used Pell and Gregory's Class II, Position B type of impacted teeth [18,19], and four studies specifed only similar types of impacted teeth were taken up for trial without specifying the classifcation category [17,[20][21][22] and one study [14] did not report on the selection criteria for including the type of impacted teeth in the study.

Pain Evaluation.
Five studies reported the pain evaluation employing a visual analogue scale (VAS) on a score of 0-10 [18][19][20][21][22], one trial reported pain evaluation by VAS score with calibration of 0-100 [14]. One trial used the number of rescue analgesics used as a means to assess postoperative pain [14]. Pooled analysis for pain scores for day 1 and day 3 was only possible from two studies [20,22] ( Table 3). Tere were no signifcant diferences in the estimated average standardized mean diference between methylprednisolone and dexamethasone for pain on day 1. Tere was no signifcant amount of heterogeneity ( Figure 2).
Similarly, there were no signifcant diferences in the estimated average standardized mean diference between methylprednisolone and dexamethasone for the pain on day 3, with substantial heterogeneity (Figure 3).

Trismus Evaluation.
In one trial, the absolute maximum mouth opening (MMO) was reported without mentioning the specifc unit of measurement. Hence, it could not be considered for analysis [17]. Two studies reported the absolute MMO values for day 2 and day 7. However, no analysis could be conducted due to insufcient data [14,22]. Four studies evaluated trismus by a change in the MMO from baseline values obtained from preoperative data [18][19][20][21] (Table 4).
Two studies involved submucosal administration of the drugs [20,21]. Te estimated standardized mean diference for the drugs administered through the submucosal route was −0.77, whereas two studies involved the administration of the drugs orally [18,19]. Te estimated standardized mean diference for the drugs administered orally was −0.61. On cumulative evaluation, the estimated standardized mean diference between two groups for trismus was −0.69 mm   Te Scientifc World Journal 5 (p < 0.0001), which favoured dexamethasone on day 2. Tis diference even though clinically insignifcant was found to be statistically signifcant. Tere was no heterogeneity among the studies (Figure 4). However, no signifcant diference was seen in the estimated average standardized mean diference between methylprednisolone and dexamethasone on day 7 for trismus on a pooled analysis of all four studies. On subgroup analysis, in the studies involving the submucosal administration of drugs, the estimated standardized mean diference was −0.35. While for the studies involving the oral administration of drugs, the estimated standardized mean diference was −0.26. Tere was no heterogeneity among the studies ( Figure 5).

Swelling Evaluation.
Two studies reported the swelling by measurement of two lines, i.e., the canthus-gonion line and tragus-commissure line [20,21]. Two other studies evaluated swelling by the sum of three lines: Canthus-gonionline + traguscommissureline + gonion-commissure line [14,22]. However, due to a lack of data, no analysis was attempted. Tree studies evaluated swelling by measurement of three lines described by Ustun et al., i.e., canthus-gonionline + traguscommissureline + tragus-pogonion line [17][18][19]. In this, two studies reported the swelling by mean diference from the baseline value [18,19], while another reported it as a mean value [17] (Table 5). Tese two studies had a similar standardized mean diference on all follow-ups. Hence, a meta-analysis could not be performed for these outcomes.

Rescue Analgesics.
Only two studies reported rescue analgesics [17,21] (Table 6). No signifcant diference in the estimated standardized mean diference between methylprednisolone and dexamethasone concerning the number of rescue analgesics. Tere was heterogeneity among the studies (Figure 6).

Discussion
Preemptive administration of corticosteroids for M3M removal surgery efectively reduced postoperative trismus and infammation [9]. Te evidence in support of both preemptive dexamethasone versus methylprednisolone to decrease postsurgical complications of M3M surgery remains equivocal. Te previous meta-analysis concluded that dexamethasone was more efective than other oral antiinfammatory drugs for reducing swelling and trismus after M3M surgery [23]. Another meta-analysis on the evaluation of the efect of submucosal dexamethasone injection as against in M3M surgery suggested that dexamethasone was more efective for reducing postoperative complications such as pain and edema, with no signifcant efect on trismus [24]. However, another meta-analysis that evaluated the efectiveness of methylprednisolone against placebos in M3M surgery suggested that methylprednisolone signifcantly reduced pain, edema, and trismus in the early postoperative period [25]. Another meta-analysis evaluating the efectiveness of methylprednisolone against other antiinfammatory drugs showed that methylprednisolone was signifcantly better in reducing trismus after 7 postoperative days [26].
We conducted this review to evaluate the efectiveness of dexamethasone versus methylprednisolone in reducing postoperative outcomes after M3M surgery. Ngeow       Te Scientifc World Journal corticosteroid (>36 h) [28]. Concerning potency, dexamethasone is more potent, as its 0.75 mg is equivalent to 4 mg dose of methylprednisolone (equivalent to 1 mg of glucocorticoid dose). Dexamethasone has better anti-infammatory properties (30 x relative to hydrocortisone) than methylprednisolone (5 x relative to hydrocortisone) [29,30]. Evaluation of facial swelling is a relatively subjective assessment. Following surgery, swelling peaks at 48 hours and has been termed "rebound swelling" [13,31]. Diferent methods of assessment of swelling were noted among the included studies with a lack of standardized reporting. Tese methods varied in the landmarks used for taking the measurements [13,14,32]. Owing to diferent methods of swelling assessment, pooled estimates could not be calculated. Only two studies with a similar method of swelling evaluation and study parameters were used for meta-analysis. Studies by Dattatraya et al. and Alacantara et al. used 40 mg of methylprednisolone and 8 mg of dexamethasone orally. Since dexamethasone is a longer-acting corticosteroid compared to methylprednisolone, it has been reported that it is more efective in reducing postsurgical swelling [14,18,19,23]. In the two studies evaluated for metaanalysis, both studies showed that dexamethasone was more efective in reducing swelling on postoperative days 1 and 2. However, the studies had similar standardized mean diferences on all follow-ups, due to which metaanalysis could not be performed.

Te Scientifc World Journal
Trismus following third molar surgery has been attributed to pain and muscle stifness. Te inhibitory feedback on motor cortex excitability from the masseter and lateral pterygoid muscle has also been postulated as one of the possible reasons for trismus [33]. However, this theory remains controversial because of the complex functions of the trigeminothalamic and spinothalamic systems [34]. Irrespective of the mechanism, trismus following third molar surgery remains signifcant postsurgical sequelae. Corticosteroid exerts an antiinfammatory efect in the surrounding tissues around the surgical area, which can indirectly reduce the intensity of trismus. Change in the maximal inter-incisal distance from the baseline value noted prior to the procedure was the method followed by four of the studies. Te pooled data from these studies showed signifcantly less trismus in the dexamethasone group in the early postoperative period (POD 2). However, there was no signifcant difference on the 7th day post-surgery (POD 7). Tis fnding could be explained by the longer half-life of dexamethasone, which would have exerted its efect for a longer time as compared to methylprednisolone.
Prostaglandins and bradykinins are the infammatory mediators produced at the tissue injury site. Tese infammatory mediators are downregulated by the corticosteroid and, hypothetically, should have relieved postsurgical pain. Tissue injury following third molar surgery stimulates neurotransmitters (substance P, glutamate, and calcitonin gene-related peptide) from the nociceptor terminals located in the spinal cord. Te corticosteroids do not inhibit these neurotransmitters. Hence, the pain persists, albeit at a lower amplitude, despite the inhibition of the production of the prostanoid [35]. Even though diferent studies have reported diferent fndings regarding the better agent in pain control, the pooled analysis did not show any signifcant diference between methylprednisolone and dexamethasone in reducing pain in the postoperative period. Furthermore, the two studies included in the pooled analysis for pain were those conducted by Chugh et al. and Srivastava et al. Tese two studies used diferent drug administration modes but used similar doses of steroids.
Apart from using the VAS score, some authors also use the number of rescue analgesics consumed postsurgery to assess pain control [17]. Te study protocol could also afect the number of rescue analgesics consumed. Not all the studies specifed the postsurgical protocol that the patients followed. Hence, only two studies could be included in the pooled analysis to assess rescue analgesics. In their study, Kulkarni et al. and Younis specifed the concept of rescue analgesics as a postoperative pain management protocol. However, the pooled analysis did not lead to any signifcant results.
Kandamani et al. [10] compared the efcacy of dexamethasone versus methylprednisolone in managing postoperative sequelae after M3M surgery. However, they only evaluated the RCTs involving the submucosal administration of the drugs and included only two studies in their review [15,20]. In contrast, we included all the RCTs that compared dexamethasone with methylprednisolone in M3M surgeries, irrespective of the route of administration. Tis is based on the comparative efcacy of two drugs remaining the same if given by a similar route [29]. Another factor that increased the heterogeneity of the studies was the diferent doses of methylprednisolone and dexamethasone administered across various studies. Te complications associated with long-term corticosteroid therapy are well documented, including osteoporosis, infections, obesity, and hyperglycemia [36,37]. However, complications associated with a single dose of corticosteroids are rare and have been reported in studies involving intralesional injection of corticosteroids. Tese include the complications such as pain, bleeding, and allergic reaction [38]. In the studies included in the analysis, none of them reported any signifcant complication which could be attributed to the single dose of corticosteroid.
Te fndings of this systematic review show that apart from having a signifcant advantage in reducing the early postoperative trismus (day 2), dexamethasone did not have any other signifcant diference compared with similarly administered methylprednisolone in reducing postoperative pain and swelling after third molar surgery. However, more studies with large sample sizes and low risk of bias are required to see the efectiveness on pain, trismus, and swelling  with standardized assessments and follow-ups along with the inclusion of patient-reported outcomes and complications.

Data Availability
Te data used to support the fndings of this study are available from the studies reviewed in the systematic review.

Ethical Approval
Te protocol used in this study was registered with the PROSPERO (International Prospective Register of Systematic Reviews) (CRD42020161341).