Three-dimensional facial swelling evaluation of pre-operative single-dose of prednisone in third molar surgery: a split-mouth randomized controlled trial

Third-molar removal represents one of the most frequent procedures in oral surgery [1]. Although the complication rate is relatively low and transient, this surgical procedure is related to significant post-operative morbidities [2]. Surgical trauma is mainly due to a higher prevalence of bone impaction and cortical bone in the mandible compared to the maxilla and variable teeth orientation with different surgical risks [3‐5]. Compared to traditional dental extractions, mandibular third molar (M3M) surgery frequently involves post-operative inflammatory nature symptoms such as swelling, pain, and trismus [6, 7]. These symptoms should be managed and reduced as much as possible to improve the patient’s quality of life. For this purpose, many therapeutic approaches have been suggested, such as non-steroid anti-inflammatory (NSAIDs) drugs or corticosteroids administration, proteolytic agents, cryotherapy, autologous platelet concentrate application, low-level laser therapy and surgical drains [8‐13]. Among the pharmacological therapies, corticosteroid drugs are the most commonly preferred pharmaceutical agents for reducing the severity of the inflammatory symptoms after surgical removal of M3M [14]. The action of corticosteroids decreases the inflammatory phases by inhibiting the phospholipase A2 pathway. It limits the synthesis of prostaglandins, leukotrienes, and thromboxane A2-related substances. In addition, corticosteroids limit the release of lysozyme and the vasodilating action of bradykinin, reducing edema [15]. According to their duration of action, corticosteroids are classified into short-acting, intermediate-acting, and long-acting (Table 1) [16]. Although it has been reported that long-acting corticosteroids have a better effect in controlling post-operative complaints, there is evidence that long-term administration and massive dosing can induce alterations in the hypothalamic–pituitary–adrenal (HPA) axis [17, 18]. Other studies have shown that short-term therapy with short- or intermediate-acting drugs can be just as effective [8, 19]. In addition to the type of drug, the time and mode of administration play an essential role in managing post-operative inflammation [20, 21]. Although many researchers suggested one treatment choice over another, there is no consensus on the ideal therapy to reduce post-surgical sequelae after M3M removal.

This study aimed to compare the effect of a single preoperative dose of prednisone versus placebo in terms of facial swelling, trismus, and pain after surgical removal of M3M in a split-mouth randomized controlled clinical trial. Facial swelling was evaluated using an innovative three-dimensional digital technique.

The present article is reported according to the CONSORT statement and its extension for within-person randomized trials [22].

Tissue damage arising from surgical trauma in M3M removal often results in common postoperative inflammatory sequelae, such as swelling, trismus, and pain, which negatively affect the patient's quality of life, especially immediately after surgery [2]. A literature review highlights that several different approaches have been adopted to reduce postoperative inflammatory symptoms [8‐13]; among these, the use of corticosteroid drugs has been widely and deeply analyzed, and their potential benefits on the inflammatory process have been assessed [14, 16]. However, which route of administration and dosage is best for the patient remains an open question [16].

In this split-mouth randomized clinical trial, we analyzed the effects of the pre-operative use of prednisone (25 mg/os) on inflammation sequelae caused by M3M surgical removal in a cohort of 32 patients. Data were collected at two different time points, specifically at 2 and 7 days, after surgery. This study's primary outcome was to compare the efficacy of prednisone/os vs placebo in reducing facial swelling using three-dimensional qualitative and quantitative analysis. The secondary outcome was to assess the effects of prednisone/os administration on trismus and pain.

Although both groups experienced facial swelling after the removal of M3M, patients treated with prednisone (PG) showed significantly less facial swelling and pain at both T1 and T2 compared to the placebo sample (CG). However, the T1-T2 evaluation showed a greater reduction in facial swelling compared to the control group. No significant associations with trismus were observed. It is important to note that these results were unbiased both for the invasiveness and the length of the surgical procedure, as no differences between the two study groups existed in terms of surgical risk stratification (Daugela et al.) and surgical time of M3M removal. In line with our data, Tiigimae-Saar et al. conducted a prospective study showing that the administration of prednisolone can be effective in reducing edema, especially in the first four days following M3M removal surgery [19]. Similarly, Buyukkurt et al. reported that a single dose of 25 mg prednisolone could be effective compared to a placebo in reducing facial edema at 2 and 7 days follow-up [26]. The combination of low doses of prednisolone (10 mg) with NSAIDs can also reduce edema following third-molar surgery compared to taking NSAIDs or placebo alone [27]. In contrast with these papers, Kang et al. pointed out that pre-emptive administration of 10 and 20 mg prednisolone per/os was not sufficient to improve postoperative inflammatory symptoms [28]. However, the lack of significance found in this study could be due to the limited sample size and subjective data collection. Postoperative symptoms were assessed using a questionnaire in which patients reported changes in symptoms for six days after the surgical procedure [28].

In our study, we selected prednisone for the pre-surgical therapeutic approach. Prednisolone and prednisone belong to glucocorticoids and share the same mechanism of action [16]. Both drugs are rapidly absorbed after oral administration, reaching peak plasma concentration after 1 to 3 h. However, the plasma half-life of prednisone is slightly longer (3.4 to 3.8 h) than that of prednisolone (2.1 to 3.5 h) [29].

In line with preliminary studies by Kim and Yuasa, our correlations between surgery duration and facial swelling showed that a longer surgical time was significantly associated with larger edema both at T1 and T2 in the groups, with no difference between PG and CG [30, 31]. This phenomenon can be attributed to increased vascular permeability due to tissue damage and greater surgical stress [32, 33].

Pain assessment showed an increase in symptoms at T1, followed by a subsequent decrease at T2 for both PG and CG. Comparing the two patient groups, PG reported less pain than CG at both time points. According to our results, oral prednisone administration one hour before surgery was correlated with lower pain compared to placebo, especially seven days after surgery, thus improving the patient's quality of life. As shown by Acham et al., a single oral administration of methylprednisone 1 h before surgery is significantly effective in monitoring postoperative pain during the first week of follow-up [8]. These data are supported by a recent systematic review with meta-analysis where the administration of corticosteroid therapy was reported to be more effective in reducing postoperative pain compared to placebo [34].

Evaluation of maximum mouth opening revealed a significant decrease at T1, regardless of patient groups. Despite symptom improvement for PG and CG, postoperative inflammation continued to have a negative effect on mouth opening at follow-up T2 with no significant differences between the two groups. These findings are in agreement with Buyukkurt et al., who previously reported that although prednisolone administration results in a clear improvement in pain, it is not associated with better effects on post-surgical trismus than placebo [26]. Although these data are partially controversial compared to other studies in which trismus is often closely related to pain, it is important to emphasize that in our study, the participants continued to have small degrees of pain and alterations in mouth opening at the end of the follow-up.

This evidence is reported by several authors who point out an improvement in postoperative sequelae by taking corticosteroids with incomplete disappearance of symptoms such as pain and trismus beyond one week of follow-up [25, 35]. Indeed, as reported by Pedersen et al., there is only sometimes a strong correlation between improvement in facial swelling, pain, and trismus after M3M surgery [36].

The efficacy of corticosteroid-based therapy in reducing post-surgical discomfort in oral surgery has been widely investigated in the literature [14].

A literature review on M3M surgery from 2000 to 2020 clearly highlighted a high interest in the scientific research around the administration of corticosteroids and around i) the most appropriate type of drug, ii) the best administration route, and iii) the most effective dosage for the management of post-surgical inflammatory symptoms and for the patient's quality of life improvement [37]. In this context, dexamethasone (DM) and methylprednisone (MP) corticosteroid drugs appeared to be the most studied ones due to their glucocorticoid properties and minimal mineralocorticoid effects [8].

As reported in several studies, the short duration of action and moderate dosage of MP are sufficient to manage inflammatory symptoms while avoiding possible systemic complications. However, many authors prefer the use of DM due to its greater anti-inflammatory potency, its prolonged drug effect (> 36 h), or the repeated administration of steroids in the following days [38, 39]. This prevents a possible rebound of swelling on the second and third postoperative days. In this regard, data arising from our study showed that the use of prednisone did not cause any rebound of swelling. Indeed, in the case of surgical removal of M3M with conventional/moderate difficulty, short-term therapy with a single pre-operative administration of prednisone appeared to be effective, avoiding multiple and prolonged administrations as well as possible alterations of the HPA axis [18].

So far, several administration routes for corticosteroids have been proposed, including intravenous, intramuscular, submucosal, and oral. The intravenous route of administration shows the advantage of leading to a rapid increase of drug concentration within plasma; intramuscular and submucosal administration provide encouraging data on the treatment efficacy. However, the former is characterized by slow onset and increased risk of HPA axis disruption, while the latter may cause local adverse events such as tissue necrosis or abscess at the injection site [40, 41]. The enteral absorption of prednisone and dexamethasone has effectively reduced postoperative inflammatory symptoms [14, 16, 42]. From this perspective, the oral route of administration may be preferable and well tolerated by patients compared to the intravenous route.

As previously reported, the best dosage depends on the type of corticosteroid used. Despite this general concept, most of the available studies showed that a high dosage effectively manages inflammatory sequelae due to oral surgery procedures.

While Mojsa et al. showed that the submucosal administration of 4 mg Dexamethasone is necessary to manage the M3M comorbidities, Erdil et al. suggested a double dosage equal to 8 mg [17, 43]. Buyukkurt et al. indicated that the administration of 25 mg of prednisolone was well-suited to control swelling, pain, and trismus after M3M surgery procedures, while in a prospective, randomized, placebo-controlled, double-blind study with a split-mouth design, Acham et al. showed that the optimal dosage methylprednisolone for the management of M3M surgical removal-related symptoms was 40 or 80 mg [8, 26].

Moreover, in a review by Ngeow WC et al., it is reported that to achieve the same effects of 10 mg prednisolone, it is necessary to prescribe 8 mg methylprednisolone or 50 mg cortisone, or 40 mg hydrocortisone (cortisol), or 1.5 mg betamethasone or dexamethasone [16]. This suggests that the choice of drug to be used is patient-dependent and very often falls to the clinical experience of the practitioner.

The results of our study suggest that pre-emptive short-term therapy of low doses (25 mg/os) of prednisone is effective compared to placebo in the management of postoperative symptoms caused by M3M removal. This concept is in accordance with a recent systematic review suggesting that pre-operative administration of corticosteroids is clinically preferable, but without identifying the optimal dosage and route of administration [44, 45].

Overall, our study shows strengths but, at the same time, weaknesses that need to be kept in mind in order to analyze the results correctly. Starting with the strengths, to our knowledge, this is the first study evaluating the efficacy of prednisone administration prior to M3M removal through the correlation of surgical difficulty assessed by CT scan-based grading and through the analysis of outcomes with 3D facial imaging technology.

Moreover, the use of very strict inclusion criteria for the enrollment of patients, as well as the triple-blind clinical study design, are certainly other major strengths of our study.

The splith-mouth design used in our study (i.e. bilateral removal of M3M with similar position and degree of surgical risk in the same patient) is quite similar to other splith-mouth randomized clinical trials [8, 12, 13, 20, 46, 47]. The main purpose of this model is to reduce all components related to differences between the subjects examined using a cross-over study.

Furthermore, the assessment of facial edema using 3D scans is more predictable and accurate than other empirical procedures [46, 48]. Indeed, over the years, several methods have been used to assess facial edema in oral and maxillofacial surgery, but these are often inaccurate and operator-dependent [49‐52]. Although 3D stereophotogrammetry is a new approach in the evaluation of facial edema after M3M surgery, the results proposed by several studies seem to be encouraging in defining the region affected by swelling [25]. Still, face scanners can be expensive and not always available. From this point of view, the use of smartphone apps that exploit 3D stereophotogrammetry can overcome the cost problem while providing equally valid and reproducible results [53]. As assessed in many studies evaluating different three-dimensional facial scans, the use of Bellus3D FaceApp allowed us to obtain results with a high degree of accuracy at a low cost and easily reproducible [54, 55].

In particular, as highlighted by Dzelzkaleja et al., who analyzed the performance of several apps, Bellus3D FaceApp is effective in keeping face scans compliant, with simple and fast image acquisition, avoiding the deformation of the scanned model [56].

On the other hand, our study has some limitations, mainly represented by the small sample examined, including only M3Ms with simple or moderate surgical risk. A further limitation might be the lack of an objective method of pain assessment.

The results showed in this split-mouth randomized clinical trial assessed that pre-operative administration of prednisone is adequate to reduce postoperative sequelae by improving patient comfort after M3M surgery with conventional/moderate surgical difficulty.

Patients undergoing third molar surgery under local anesthesia may benefit from a single administration of low-dose prednisone. Furthermore, this administration route is simple, convenient, and comfortable for both patient and surgeon.

The digital analysis performed in our study allowed a more objective evaluation of the facial swelling, reducing costs and possible bias.

However, the authors believe that further multicenter randomized controlled trials are necessary to validate this treatment's efficacy and to extend the results at all types of M3M.