During the past 10 years, the commonly studied corticosteroids for use in third molar surgery were dexamethasone (17 reports), methylprednisolone (10 reports), prednisolone (2 reports) and betamethasone (1 report). Four other studies compared two different steroids. Corticosteroids had been administered via various routes that included intravenous, intramuscular (masseter, deltoid or gluteus), submucosal, endo-alveolar and oral.
Results Involving Dexamethasone
Dexamethasone was first tested to control edema and to decrease trismus and pain after oral surgical procedures in 1965 , and since then, there has been a surge in popularity for its use in oral surgical procedures. It is one of the most frequently studied and used corticosteroids in oral and maxillofacial surgery [22–38] (Table 2). In early studies, it was usually given intramuscularly, and Messer and Keller  were of the opinion that the masseter muscle made a good site to receive injections because of its proximity to the third molar surgical site.
Fast forward to this millennium, newer methods of delivery have been adopted. Graziani et al. in 2006 compared the efficacy of dexamethasone given as submucosal injection and endo-alveolar application . This study showed a significant reduction in swelling following the administration of submucosal dexamethasone and the placement of endo-alveolar dexamethasone post-surgically. It was reported that endo-alveolar application of 4 mg dexamethasone significantly reduced trismus but this was not the case with submucosal injection. In addition, the low-dose dexamethasone powder applied endo-alveolarly reduced post-operative pain significantly when compared to others. This study introduced the endo-alveolar approach for administrating corticosteroid which has the benefit of easy placement, and providing a localized effect with reduced systemic side effects of corticosteroids. A further study on endo-alveolar application was later performed once and this study confirmed its benefit .
The following year, Grossi et al. compared the efficacy of increasing the dosage of dexamethasone to 8 mg, as compared to the 4 mg used by Graziani et al. [22, 24]. Submucosal injection was given at the buccal tissue adjacent to the surgical site and was usually given after local anesthesia of the area had been achieved. This technique was easy and safe to perform, comfortable to patients and produce a localized more than a systemic one . Grossi et al. found no significant difference between the dexamethasone and the control groups in reducing post-operative pain and trismus, although submucosal dexamethasone resulted in significantly less facial swelling on the second day post-operative . The latter finding was supported by a post-operative symptom severity (PoSSe) scale with the control group reporting more changes in appearance than the study group. They concluded that 8 mg dexamethasone was not superior to 4 mg dexamethasone and recommended the use of the lower dose of dexamethasone to reduce post-surgical sequelae following third molar surgery. This recommendation concurs with that suggested by Graziani et al. .
Using the enteral approach, Laureano Filho et al. in 2008 compared the efficacy of different doses of dexamethasone given 1 h pre-operatively . They found a significant reduction of post-operative sequelae with the use of a higher dose, i.e. 8 mg of dexamethasone. The finding from this study differed from that reported by 2 previous authors who reported no significant benefit of giving a high dose of dexamethasone [22, 24]. As the corticosteroid was given via an enteral route, it has to undergo absorption in the gastrointestinal tract. So a higher dosage will definitely provide a higher load factor following absorption. This finding is in contrast to an early study half a century ago when Linenburg reported that an even lower dose 3 mg of oral dexamethasone, taken as 3 divided doses over 2 days, with the first dose taken 1/2 h pre-surgery, was effective in reducing swelling and trismus . Do note, however, that Laureano Filho et al. gave only one single dose, as compared to Linenberg’s sustained prescription over 2 days. Despite the significant findings of Laureano Filho et al.’s work, a conclusion as whether oral 4 mg dexamethasone was significantly effective could not be made since there was no negative control in this study .
Majid presented 2 reports on the effects of dexamethasone in 2011. In one of the reports, which was co-authored with Mahmood, he compared the effect of submucosal and intramuscular injection of 4 mg dexamethasone after third molar surgery in 30 subjects . Both routes produced significantly less swelling and pain than control. Submucosal dexamethasone was also reported to significantly reduce trismus on the first post-operative day. They suggested that submucosal injection had the advantage of reducing trismus because of its localized effect. Since both routes of administration provided the same results with regards to swelling and pain, they were of the opinion that the submucosal route might perhaps be a better choice due to its ease of administration and the localized effect at the surgical site. The small sample size (10 subjects per study group) was the main limitation of this study. However, a subsequent study with a 50% larger sample using the same combinations 4 years later showed that the submucosal route was indeed more effective in minimizing not only post-operative trismus but also swelling and pain, than intra-muscular (deltoid) injection . Majid increased the number of subjects to 11 in each study group to arrive at a second report, which also studied the effect of submucosal and intramuscular injection of dexamethasone after third molar surgery on patients’ clinical sequalae. He added the measurement on the quality of life (QoL) . The results were found to be similar to the earlier study, where both submucosal and intramuscular injections of 4 mg dexamethasone given just after surgery resulted in significant improvement of swelling and pain, and also in QoL measures when compared to control. Like the previous study, only the submucosal group showed significant improvement of trismus when compared with control. Majid concluded that submucosal dexamethasone offered significant positive effects on clinical and QoL recovery.
In the same year, Deo and Shetty studied the efficacy of single submucosal injection of a higher dose (8 mg) of dexamethasone given prior to third molar surgery . They found that dexamethasone was significantly effective in reducing swelling and trismus on the second day post-operative. Dexamethasone also prolonged the duration of analgesia, resulting in the dexamethasone group consuming their first analgesic significantly later than the control group. However, there was no overall significant difference in pain perception between the study group and saline control. The limitation of this study was the fact that both groups of samples were given ice-pack and ibuprofen post-operatively. This may explain why no difference in pain perception was observed post-operatively, as the anti-inflammatory effect of ibuprofen is more efficacious for pain control purposes. Elsewhere, a randomized controlled trial was carried out by Antunes et al. to compare the efficacy of 8 mg dexamethasone administered using 2 different routes, oral versus intramuscular (masseter) injection . They found no significant differences between the two dexamethasone groups in reducing post-operative pain, swelling and trismus, where both modes were better than control group. The advantage of intramuscular masseter injection would be its close proximity to the surgical site, hence possibly providing some localized effect although it cannot be ruled out that this injection provided a systemic effect equal to oral dosing .
In 2012, Boonsiriseth et al. reported an almost similar approach in a study that compared the efficacy of intramuscular dexamethasone and oral dexamethasone in reducing the sequelae of third molar surgery . The only difference was that the intramuscular injection was given into the deltoid muscle which was a distance from the oral cavity. Hence, the effect of dexamethasone was purely systemic. They found that no significant difference was noted between both groups, similar to the report by Antunes et al. . Based on the findings of these 2 studies, it appears that the anti-inflammatory effect of intramuscular dexamethasone was more likely to be of systemic rather than local effect, as the absorption of dexamethasone via the masseter and deltoid muscle produced similar effects. Klongnoi et al. conducted a study to investigate the effects of intramuscular dexamethasone given 1 h pre-emptive in reducing pain, swelling and trismus . Pain and swelling were significantly reduced with corticosteroid but it was not effective in reducing trismus . Although intramuscular administration into the deltoid muscle was easy and accessible, it is painful, and absorption varies depending on local blood flow.
In the following year, Bortoluzzi et al. studied the incidence of post-operative complications of alveolar osteitis and alveolar infection, in addition to the usual sequalae following third molar surgery . They used two drugs, namely oral 8 mg dexamethasone and 2 g amoxicillin, in various combinations where either of both the drugs can be present or absent altogether. In essence, there was a group with both drugs present, 1 group with dexamethasone, 1 group with amoxicillin and 1 group where neither drugs were given. Surprisingly, they found no significant difference between groups in terms of post-operative swelling, pain and trimus. This may have been caused by the use an ice-pack and the prescription of paracetamol and sodium diclofenac as post-operative analgesics. In addition, the measure of swelling and trismus were based on patient reporting. As no clear benefit could be observed, they recommended that antibiotic and corticoid prophylaxis should not be administered routinely for third molar surgeries involving healthy and young patients.
In the same year, Nair et al. and Warraich et al. conducted independent studies at two different centers to evaluate the efficacy of pre-emptive 4 mg dexamethasone given as submucosal infiltrations [33, 34]. While both authors concluded that this regime significantly reduced post-operative swelling, they differed in reducing pain and trismus. Warraich et al.  found dexamethasone was significantly beneficial in reducing pain and trismus. Their patients also reported increased satisfaction with the use of dexamethasone , probably because these patients suffered less from the sequelae of third molar surgery. The post-operative regime of analgesic prescribed may have contributed to the difference in the findings of trismus and pain between these 2 studies. Nair et al. prescribed diclofenac sodium 75 mg twice a day for 3 days, while Warraich et al. prescribed ibuprofen 600 mg 3 times a day on Day 1, twice a day on Day 2 and once daily on Day 3 and Day 4. In contrast to Warraich et al.’s regime, the constant dosage in Nair et al.’s study produced sustained plasma level of analgesic which rendered better pain control and subsequently improved the ability to open the mouth in both the study and control groups. This may cause the study group to report no additional beneficial effect of dexamethasone when compared with the control.
In continuity to their earlier work, Majid and Mahmood  became the first researchers to compare the effect of giving post-operative dexamethasone using 5 different routes of administration, namely intramuscular injection, intravenous injection, oral tablets, submucosal injection and endo-alveolar application. They reported no significant differences among groups for all the parameters of swelling, pain and trimus in subjects given 4 mg dexamethasone. They found that, to control swelling, the best improvement was obtained via the intravenous route, followed by the intramuscular, submucosal, oral and endo-alveolar routes in a descending order on the first post-operative day. Interestingly, they found that the endo-alveolar group showed better improvement on Day 3. In comparison, the submucosal route provided slight advantage on Day 1, although the effect on trismus was comparable among treatment groups. Again, they found that endo-alveolar dexamethasone showed a better effect on trismus at the subsequent intervals of Day 3 and Day 7. With respect to pain, intravenous administration was reported to be the best at all intervals, followed by endoalveolar, submucosal, oral and intramuscularroutes in descending order. In summary, their results seemed to favor the intravenous and endo-alveolar routes, although other means of administration appeared to provide comparable results.
In 2014, another study similar to Nair et al.’s and Warraich et al.’s was undertaken by Ehsan et al. to examine the pre-emptive effect of submucosal infiltration of 4 mg dexamethasone on post-operative swelling and trismus only . Their findings support the results reported by Deo and Shetty and Warraich et al., but Ehsan et al. did not study the effect of dexamethasone on post-operative pain and their analgesic regime was not described. In the same year, Agostinho et al. compared the effect of 4 mg and 12 mg dexamethasone in reducing post-operative sequelae . The latter dosage was three times the lowest effective dosage of 4 mg reported elsewhere. Their findings concurred with that reported by Grozzi et al. and Graziani et al. where a higher dosage of dexamethasone did not offer a better outcome. Thus, based on their findings, they suggested that the lowest dose possible to achieve an anti-inflammatory effect should always be prescribed.
Recently, Chaudary et al. compared the pre-emptive effect of 4 mg intravenous dexamethasone against an oral administration of 8 mg dexamethasone . They found that both routes of administration were equally effective in reducing post-operative pain, swelling and trismus. This is because an oral corticosteroid such as dexamethasone at 8 mg has a very high enteral absorption rate that is comparable with intravenous application . Hence, oral dexamethasone is a good alternative to the intravenous route in patients who do not wish to receive an injection.
Over the last decade, only 1 study has looked into the effect of betamethasone. Marques et al. in 2014 studied the effect of a post-operative submucosal betamethasone 12 mg injection on the sequelae of third molar surgery . Surprisingly, betamethasone which is of the same potency as dexamethasone showed no significant effect in reducing post-operative swelling, pain and trismus at all. This finding is in contrast to that reported by Chopra et al. who studied the effects of several drugs, one of which was betamethasone, given orally three times a day following third molar surgery . We disagree with the authors’ proposal that tissue manipulation affected the concentration and absorption of the injected drug as one of the explanation for their findings, since the injection was given after the surgery, where no further tissue manipulation was carried out. We agree with the authors that more study on the effect of betamethasone needs to be carried out to ascertain its effects in reducing post-operative sequelae since betamethasone has the same potency as dexamethasone, and therefore should theoretically render similar results clinically.
In summary, dexamethasone has proven to be an effective agent for reducing pain, swelling and trismus to a certain degree, irrespective of the route and the timing of administration. The lowest dose possible to achieve an anti-inflammatory effect was 4 mg. No serious adverse effects, namely acute alveolar osteitis, post-operative infection and nausea, have been reported following the administration of dexamethasone in the study samples. Variations in the results may be because of differences in surgical methods, differences in individual response to treatment and differences in the methodology used.
Results Involving Prednisolone
Prednisolone and methylprednisolone have been tested in a number of studies (Table 3) [39, 41–51]. Two reports coming from the 1970s showed that preemptive administration of intravenous methylprednisolone or oral prednisolone significantly reduced post-operative edema, pain and trismus [52, 53]. Prednisolone and methylprednisolone are five times more potent than cortisone, with an intermediate duration of action (see Table 1). Prednisolone is available in oral, topical and injection forms, while methylprednisolone is usually administered via the intravenous or intramuscular route [41, 42]. Although the possibility of topical (endo-alveolar) application has been described for dexamethasone, this approached has yet to be attempted on prednisolone.
Throughout the last 10 years, only 2 studies have looked into the effects of prednisolone. Tiigimae-Saar et al. reported that post-operative administration of 30 mg prednisolone relieved pain, swelling and trismus more than non-administration of prednisolone in the control group . On the other hand, Kang et al. tried to determine the effect of lower doses of prednisolone on the sequelae of third molar surgery . They compared the efficacy of 10 mg and 20 mg prednisolone taken orally in more than 200 patients. Their results showed that both dosages had no significant impact on the sequelae of surgical removal of third molars. Hence, they concluded that a dosage of 20 mg or lower may not provide relief of post-operative sequelae. It is suspected that such a finding may have resulted from the use of ice-packs for 2 post-operative days and the prescription of ibuprofen 200 mg orally preoperatively, immediately after surgery, and every 8 h until the third post-operative day, which masked the effect of prednisolone. In addition, this study was carried out by the use of a questionnaire with patients being asked to report changes in post-operative symptoms for 6 days .
There have been 12 studies that attempted to determine the effects of methylprednisolone on the sequelae of third molar surgery. In 2006, Micó-Llorens et al. conducted a study to determine the efficacy of pre-operative gluteal injection of methylprednisolone in controlling the sequelae of third molar surgery . They reported that methylprednisolone significantly reduced post-operative swelling and trismus on the second post-operative day. As for post-operative pain, its significant effect was only recorded at 6 h post-surgery. Subsequently, the pain difference between the methylprednisolone group and control was not significant. Gluteal injection may be effective but this method may not be convenient in certain clinical settings. Two years later, the same group, now lead by Vegas-Bustamante, performed a similar study, but instead gave post-operative masseteric injection of 40 mg methylprednisolone . They found that this regime significantly reduced post-operative swelling and trismus for up to 7 days, and provided better pain control for 3 days post-operative.
In the following year, Gataa and Nemat compared the effectiveness of two modes of pre-emptive administration of 10 mg methylprednisolone, namely enteral and submucosal injection . They reported that methyprednisolone taken orally 1 h pre-operative was more effective than submucosal injection in controlling swelling and pain. They reasoned that this was due to the slow absorption of the injected form of methylprednisolone, coupled with its biological half-life of 18–36 h. As pain usually peaks 6–8 h and edema reaches its maximum size about 36–48 h after third molar surgery, the injected (localized) methylprednisolone therefore has less effect due to the slower onset of its action. This suggestion, however, needs further investigation as the only other group of researchers who investigated the effectiveness of submucosal injection of methyprednisolone after them reported contradictory results. Ashraf et al. reported that submucosal injection was equally as effective as intramuscular (gluteal) injection in providing relief of swelling, pain and trismus after third molar surgery . Do note, however, that they administered a high dose of 125 mg methylprednisolone to their patients, probably because they were influenced by the dose used by Al-Khateeb et al. . Besides them, the only other authors who compared the effect of submucosal and intramuscular injection were Majid and Mahmood both reporting favorable effects on swelling and pain using dexamethasone, but at a lower equivalent dose [23, 26].
In 2011, Kaur et al. conducted a study similar to that performed by Vegas-Bustamante et al. to evaluate the effect of a single 40 mg dose of methylprednisolone, injected into the masseter muscle following surgical removal of impacted third molars . They also reported that methylprednisolone had significantly reduced post-operative pain, swelling and trismus. The findings from 3 studies confirmed that masseteric injection is a good and effective way to administer methylprednisolone [41, 42, 45]. This observation was confirmed in 2013 by Chaurand-Lara and Facio-Umaña who reported that the benefit of giving a masseteric intramuscular injection of 20 mg methylprednisolone for immediate post-operative control of pain and swelling . The limitations of their study were that the site of this split mouth study was not randomized and only the subjects were blinded to the injection.
Acham et al. were the only authors who studied the effect of pre-emptive body weight-dependant doses of oral methylprednisolone in reducing post-operative pain, swelling and trismus . The reason why they administered methylprednisolone orally was because of its extremely high enteral absorption rate that is comparable with intravenous application. Similar to the results obtained from previous studies using methylprednisolone, it was significantly effective in reducing all 3 post-operative sequalae, especially pain. There was significantly less pain suffered by patients given methylprednisolone throughout the 7 days of study. They acknowledged the use of NSAIDs post-operatively may partly contribute to this good result. The authors reported no adverse effect related to the drug, but the fact that patients were covered with pantoprazole made it difficult to find any gastrointestinal effect of relatively high doses of methylprednisolone.
Koçer et al. in 2014 attempted to determine the best route for prescribing effective methylprednisolone . They compared the efficacy of 20 mg methylprednisolone in reducing post-operative swelling and trismus delivered through masseteric intramuscular injection, oral intake and intravenous delivery. They reported less trismus in all patients given methylprednisolone regardless of its forms or routes. Of these routes, masseteric (local) injection proved to be superior in reducing swelling but trismus was slightly better controlled by intravenous methylprednisolone, although this finding was not statistically significant. From these findings, we can deduce that masseteric injection of methylprednisolone would make a good mode of administration taking into consideration the ease of administration, patient comfort and its better post-operative effect . Results from this study reconfirmed the findings of 4 previous studies.
Instead of the mode of administration, Vyas et al. studied the timing of drug administration . They compared the pre-emptive and post-operative effects of intramuscular methylprednisolone and reported that pre-emptive administration of 40 mg methylprednisolone was significantly better in reducing facial swelling and trismus and, to some extent, pain . Pre-emptive methylprednsolone provided early advantage in pain relief, but later was not different than post-operative intramuscular injection as the latter become redistributed in the circulation. These findings were not unexpected as corticosteroids were given 1 h before the onset of inflammatory response, thereby allowing adequate time to reach the target site to prevent the activation of the arachidonic acid pathway following injury . Methylprednisolone acetate used in this study has a sustained release effect due to its formulation, thus providing a prolonged anti-inflammatory effect that prevented rebound swelling from happening. In this study, no negative control was used, therefore anti-inflammatory effect of post-operative administration of methylprednisolone cannot be entirely appreciated, unlike in the reports by Vegas-Bustamante et al.  and Kaur et al. .
Selvaraj et al. in 2014, compared different sites for intramuscular injection. They injected 40 mg methylprednisolone into masseter and gluteus muscles of the same subjects undergoing a cross over study and found no significant difference in the effects when using these two sites . Both sites of administration were equally effective in reducing patients’ post-operative sequalae of swelling, pain and trismus. This finding supports the suggestion of the systemic effect of intramuscular injections of corticosteroids as shown by Boonsiriseth et al.  and Antunes et al. , who found that the absorption of drugs via the masseter and deltoid muscles produced the same effect as oral intake. This again supports the suggestion that the effect of masseter muscle injection is systemic instead of localized. So, if given a choice between the masseter and other sites, it is more likely that the masseter will be the preferred site of injection as it is more convenient and comfortable to the surgeons and patients. It also holds the advantage of being a painless site for steroid injection as the masseteric muscle usually gets anesthetized during the provision of local anesthetic agents for third molar surgery.
In summary, prednisolone and methylprednisolone have proven to be effective agents for reducing swelling and trismus, and to some extent pain, irrespective of the route and the timing of administration. The lowest dose possible to achieve anti-inflammatory effect appears to be 40 mg. No serious adverse effects, namely acute alveolar osteitis, post-operative infection and nausea have been reported following the administration of prednisolone or methylprednisolone in the study samples. Variations in the results obtained may be the results of differences in surgical approaches, differences in individual response to treatment and differences in the methodology adopted.
Result Comparing Different Corticosteroids
For some unknown reasons, there are few studies that have attempted to compare the efficacy of two different groups of corticosteroids (Table 4). So far, there have been 3 studies undertaken to compare the efficacy of dexamethasone versus methylprednisolone in controlling the post-operative sequalae of third molar surgery [54, 56, 58]. In 2012, Loganathan and Srinivasan  compared the efficacy of single doses of methylprednisolone (40 mg) and dexamethasone (4 mg) injected into the masseter muscle about 15 min prior to surgery. They found no significant difference between the two groups in alleviating the post-operative sequale of third molar surgery.
In contrast, Alcântara et al. and Darwade et al. reported different findings [54, 57]. Both studies compared the efficacy of oral administration of 8 mg dexamethasone against 40 mg methylprednisolone in reducing post-operative discomforts. These dosages were chosen as they were approximately equivalent to 200 mg of cortisol. Both studies reported significant reductions in swelling and trismus in the dexamethasone group as compared to the methylprednisolone group. The former group was also reported to have less pain when compared to the methylprednisolone group, although the difference was not statistically significant. The beneficial effect of dexamethasone was due to its longer duration of action and greater potency compared to methylprednisolone.
Most recently, Zerener et al.  has compared the post-operative submucosal injection of dexamethasone and triamcinolone acetonide. This is the only study that has tried to determine the effect of injecting triamcinolone acetonide submucosally. In agreement with many other studies, both corticosteroids were significantly better in controlling post-operative swelling. Dexamethasone was better in reducing post-operative pain and trismus on the first and third post-operative days, while triamcinolone acetonide controlled pain better on the third and seventh post-operative days compared to control. Triamcinolone acetonide significantly reduced trismus throughout the period of assessment compared to control, while dexamethasone was effective during the early post-operative days. The difference in the time of best effect may have resulted from the different half-life of each steroid. However, there was no significant difference between the two corticosteroids in reducing post-operative swelling, pain and trismus. Nevertheless, the authors suggested that triamcinolone acetonide makes a good alternative to dexamethasone in controlling the post-operative sequale of third molar surgery.
In summary, more studies should be carried out in the future to compare different types of corticosteroids to reveal the one with the lowest effective dosage and easiest route of administration for use in routine oral surgical procedures. Dexamethasone appears to be more potent and effective than methylpredinsolone clinically. The use of triamcinolone acetonide though is promising, and needs further randomized and control studies. A summary of the outcomes of various researches cited here is presented in Tables 2, 3 and 4.