EFFECT OF VARIOUS ROUTES OF ADMINISTRATION OF METHYL PREDNISOLONE ON SWELLING, TRISMUS AND PAIN IN IMPACTED MANDIBULAR THIRD MOLAR SURGERY

Amartya Prakash Srivastava,Ravinder Singh Bedi, Jitender Kumar Aurora, Puneet Wadhwani, Himanshu Chauhan, Aprajita Srivastava and Shrikant Chakrawarti. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 21 July 2018 Final Accepted: 27 August 2018 Published: September 2018

Extraction of third molar by surgical approach is very common procedure performed by maxillofacial surgeons. Swelling, trismus and pain are contemplated as transient postoperative complications regarding this procedure as soft tissue and hard tissue both undergo violation followed by relase of inflammatory mediators.
Corticosteroids inhibit phospholipase A2 enzyme, which diminishes arachidonic acid release. Thus, prostaglandins and leukotrienes are less synthesized along with reduction in accumulation of neutrophils (Hirschman 1986).
Traditionally, dexamethasone and methylprednisolone are more often used as they are 4-5 times more efficacious than the natural compound cortisol and can be administered orally or IM or IV.
Methylprednisolone possess least mineralocorticosteroid activity and attains a therapeutic plasma level within initial postoperative days and have been utilized in different molecules, vivid dosages, routes and time of administration.
Only a few studies have been done for efficacy comparison of methyl prednisolone when administered alone by various routes. While many studies have documented the use of 40-80 mg methylprednisolone, we administered methylprednisolone 20 mg considering the adverse effects found in these studies. Present study aimed to weigh the efficacy of methyl prednisolone on swelling, pain and trismus on peculiar days following mandibular impacted third molar extraction.

Material and Methods:-
This study was a randomized, prospective, and controlled study. The patients reporting to outpatient department of Oral and Maxillofacial Surgery, Saraswati Dental College & Hospital, Lucknow (U.P) between January 2016 to November 2017; in whom surgical removal of impacted mandibular third molar was indicated, were thoroughly assessed in terms of inclusion and exclusion criteria. Among the patients who satisfied the criteria, a total number of 48 patients were randomly selected. Individuals of both genders of age group between 18-45 years were selected irrespective of their religion, cast, race or socioeconomic status.
Healthy patients aged between 18 to 45 years devoid of systemic disease having impacted lower third molars with any combination of class I, II position A and B( as per Pell-Gregory classification) were included.
Patient having any medications (Erythromycin, Clarithromycin, or Troleandomycin) that could interfere with methylprednisolone, adverse habits like smoking and conditions like pregnancy or lactation were not included in the study.
This study was undertaken after obtaining approval from the "Institutional Research and Development Committee" and "Institutional Human Ethical Committee" of Saraswati Dental College & Hospital Lucknow. All selected patients were informed about the purpose and experimental nature of the study. A written informed consent was obtained from the study subjects for participation in the study. General health of the patients was evaluated by taking detailed history, thorough clinical examination, hematological and radiological investigations preoperatively. Patients were picked randomly and recruited among four groups.
Thus 12 patients constituted as group I or control group. In the same fashion, 3 study groups of 12 patients each were assigned and termed as group II, III, and IV respectively in following manner. Group I-Control group-In this group, steroids were not administered. Group II-IM group-In this group, 0.5 ml of 40mg/2ml methyl prednisolone acetate; constituting 20mg was administered in masseter muscle via intra-buccal approach 1 hour pre operatively. Group-III-I.V group In this group, Intra venous administration was done by injecting 0.5 ml of 40mg/2ml methylprednisolone succinate constituting 20mg, one hour before the procedure. Group IV-Oral group-In this group, oral administration of methyl prednisolone Tab 20mg 1hour before procedure as a single dose was done.
Pain was evaluated using a 15cm long handmade numeric and pictoral visual analogue scale (VAS) ranging from 0 to 10 indicating no pain to worst pain respectively.
Maximal inter incisal opening was evaluated by measuring the gap between incisal edges of upper & lower central incisors at unassisted full mouth opening using carbon fiber composite made digital vernier's caliper (Accuracy 0.1mm or 0.01 inch, noncontact linear CAP measuring system with LCD display CR20323V/SR44/LR44) Swelling was evaluated using mean of 2 facial lines- (Fig 1) 1. Distance from lower border of tragus to the soft tissue pogonion (T-P) 2. Distance between external canthus of eye to the gonion angle (C-G) All three parameters were assessed for each patient on pre-operative, 1st, 3rd, 7th and 14th post-operative days respectively.
In patients of Intramuscular group; drug was administered using 2ml syringe fitted with 24 guage needle. Injection was given into the mid-region of the masseter muscle, in such a manner that the syringe being above and parallel to the occlusal surfaces of the mandibular molars. In patients of I.V group, methylprednisolone succinate was administered in subclavian vein considering antecubital fossa.
All the patients were given pre medication (Tab. Amoxicillin with clavulanic acid 625 mg) a night prior as per the requirement. Patients were told to gargle with 0.2% chlorhexidine gluconate mouthwash for 2 minutes prior to administration of local anaesthesia.
Local anaesthesia was attained by administering 2% lignocaine hydrochloride with adrenaline (1:200000) as inferior alveolar nerve block supplemented by lingual and long buccal nerve block.
Ward's incision was marked and placed. To raise a full thickness mucoperiosteal flap. The buccal guttering was initiated at a fixed RPM under copious irrigation using 0.9% normal saline followed by elevation of impacted tooth. Extraction process was completed using extraction forceps. The socket was then curretted and the boney spicules, if any, were removed. Socket was irrigated with povidone iodine diluted in normal saline (1:4). Primary closure was achieved by 3-0 round body black braided silk. All patients received standard post-operative instructions.
Antibiotics (Tab Amoxicillin and clavulanic acid 625mg/eight hourly) and 2 Tabs of Ketorol-DT 10 mg (12 hourly) were pescribed for 5 days. Patients were advised to rinse after every meal with 0.2% clorhexidine gluconate solution. Intra oral sutures were cut and removed on 7th post-operative day. To eliminate the surgeon's bias, all the procedures in all patients were performed by the same surgeon.
Statistical Analysis:-All collected data in this study were analyzed using descriptive statistics and making comparisons between two groups of treated patients, with respect to various parameters. Categorical (discrete) data was summarized in form of proportions, percentages (%) and Mean ± SD (standard deviation). Data analysis and statistical analysis was done with Statistical Package for Social Sciences (SPSS version 17.0 for windows) & MS Office Excel software for windows. The following statistics were calculated in the present analysis: The chi square test was used to find association between categorical variables.
The one-way analysis of variance (ANOVA) was used to evaluate any significant differences among the means of various (more than two) independent groups. Bi-group comparisons were performed by Tukey HSD (honest significant difference) test.The level of significance was set as P < 0.05 for each parameter.

Results:-
The mean age of control group patients, IM group patients, IV group patients and oral group patients was 26.33±8.57 years, 26.50±5.85 years, 26.08±7.43 years and 27.17±6.66 years respectively. According to ANOVAtest no statistical significant difference (p=0.985) was found among the mean ages of the groups. Hence the age of the selected subjects was almost indifferent for each group.
The female -male ratio of the control group, IM group, I.V group and Oral group was 41.7: 58.3 %, 25.0: 75.0%, 25.0 : 75.0% and 33.3 : 66.7% respectively. On application of chi square test, no significant difference was found in the female-male ratio among the four groups (p=0.785) statistically. Hence the subjects selected were gender matched for the four groups.
The mean difficulty index of control group patients, IM group patients, I.V group patients and Oral group patients was 3.92±0.67, 4.83±1.59, 4.83±1.27 and 4.58±1.17 respectively. On applying ANOVA-test, no statistical significant difference (p=0.223) was found among the mean difficulty indices of the groups. Hence the subjects selected for the four groups had same level of difficulty regarding extraction.
Swelling, Trismus and Pain:-In our study on 1 st and 3 rd postoperative day, statistically significant reduction of swelling with respect to control group was observed among all the study groups. However the mean increase in swelling on 1 st and 3 rd postoperative day was least in IM group whereas it was profound in control group. On 7 th postoperative day, the mean increase in swelling was least in IV group whereas prominent in control group. Rest of the intragroup comparison revealed no statistical difference in reduction of edema (Tab 1).
The interincisal opening decreased on 1st, 3rd, 7th postoperative day in all groups. However the magnitude of reduction in mean mouth opening was statistically significant in only IM group patients on 1st postoperative day. The decrease in the mean mouth opening on 3rd post op day was most prominent in control group and was least in IM group. On 7th, and 14th postoperative day rest of the intragroup comparison revealed no statistically significant discrepancy in terms of mean mouth opening (Tab 2).
The postoperative pain was less in study group as compared to the control. On first postoperative day, there was marked increase in pain in patients of control group whereas least pain was reported in IM group which was statistically significant. However there seemed to be no statistical difference in post-operative pain among all the four groups on the 3rd and 7th day. Although IM administration seemed to be comparably more efficacious than other routes in reduction of post-operative pain but the difference was statistically insignificant. On 14th postoperative day in our study, with respect to control group, all other groups proved to be better in terms of mean pain score while IM, IV and Oral group provided almost similar results (with a negligible difference of 0.08 on VAS score). It may be due to shorter half-life as well as single dose of the drug. (Tab 3)

Discussion:-Swelling
Postsurgical edema is tough to quantify appropriately because it entails three dimensions of measurement with an convex and uneven surface, and might manifest itself internally and externally. As subjective observation is concerned, lean patients seem to have extra swelling than sufferers who are "plump," "stout," or overweight (Messer and Keller 4 ). They also stated that redheaded, blonde, and fair-skinned patients are more prone for swelling as compared to dark-complexioned patients. The precise duration of edema in response to surgical procedure in oral and maxillofacial region is not well documented and is probably variable for each patient and procedure. Laskin states that edema is maximum on 24 to 48 hours, but Peterson says it is maximum on 48 to 72 hours and usually resolves after 7 days.He further stated that any swelling after operation which keeps on expanding after 3 days, is not postoperative selling but it may be associated with infection.
A time span of 2 to 3-days is most frequently cited and is consistent with various published studies.Huffman et al 7 reported a statistically significant reduction in edema in patients who were administered 125 mg of intravenous methylprednisolone immediately before surgery, but after 7 days there was no difference noted.
Hargreaves and Costello observed 62% reduction in release of immune reactive bradykinin, 3 hours after surgery when 125 mg of methylprednisolone was used.
Pedersen A et al 8 noted a 50% depletion in swelling on the second postoperative day when 4 mg of intramuscular dexamethasone was used but no significant difference on the seventh postoperative day was noted.
When a single dose of 20 mg methylprednisolone was used preoperatively, Milles and Desjardins 9 noted a 42% reduction in swelling on the first postoperative day, 34% less on the second, but only 19% less on the third postoperative day.
Various studies have used various methods for the measurement of oedema, like computed tomography, malleable metal rods, etc. Other modalities like clinical observation, subjective palpation, compass, photographic techniques , stereophotography has also been applied to assess the amount of swelling. Actually each method has its own pros and cons.
According to Emin Esen et al 10 ultrasound and CT are among the most accurate diagnostic techniques. These techniques made it possible to perform precise measurements of the facial soft tissues. However, during examination of the soft tissue with ultrasound, some alterations can occur in the measurement because the transducer is applied with a slight pressure.
The method we used in our study to measure facial swelling (stickers and silk thread embedded with stoppers) is a modification of Mastumara et al 11 It is also easy to use, inexpensive, valid and convenient for repeatability of the method.
Our study demonstrated similar findings where postoperative edema was consistent till 3 rd postoperative day among all four groups and the results were highly significant (p< 0.001), however all groups (IM, IV and oral) were significantly efficacious in reducing postoperative edema on 1 st and 3 rd postoperative day as compared to the control group. But no significant difference among all four groups was noted on 7 th and 14 th postoperative days in intra group comparison.

Trismus
In this study, we have preferred to use digital vernier caliper over mechanical caliper owing to its better accuracy. The mean reduction in inter-incisal opening on first post-operative day for all three groups of methylprednisolone was observed to be 14.83 % as compared to control group. Statistically significant findings have been ducumented when corticosteroids are used in combination with drugs like Diclofenac potassium for reducing pain and swelling, but not in reference to trismus by Bamgbose BO et al 12 López-Carriches C et al 26 in his study using methylprednisolone and diclofenac, concluded that the trismus may retain for up to 10 days after surgery.
In studies of Moore et al 13  In a study performed by Vaibhav et al 20 , where he compared the efficacy of intravenous, intramuscular (in masseter muscle), submucosal and oral routes of administration of 20 mg methylprednisolone for decrease in postoperative trismus in patients undergoing lower 3 rd molar surgery. He found no statistically significant difference in mean inter incisal opening on 2 nd and 7 th postoperative day (p = 0.37), (p = 0.29) while in our study, intra group comparison showed statistically significant difference (p=.048) in mean inter incisal opening on the 1 st postoperative day. Although no significant difference was noted on the 3 rd , 7 th and 14 th postoperative day among all groups however inter group comparison showed intramuscular route to be significantly (p = .044) more efficacious in reducing trismus on 1 st postoperative day. Whereas all routes of administration showed no significant difference when compared to the control group on 3 rd , 7 th and 14 th postoperative day.
In a study done by G. Koger et al 21 it was observed that mouth opening following the masseter injection, i.v. injection and oral tablet of methylprednisolone on postoperative days 2 and 7 was significantly greater than in the control group (P < 0.05). Among the groups, mouth opening was greater in the i.v. injection group compared to the oral tablet and masseter injection groups on day 2, although the results were statistically insignificant (P > 0.05). In our study, it coincides with results of first postoperative day where all groups were significantly efficacious in improving postoperative mouth opening when compared to control group in which inter incisal opening was significantly reduced (p=0.048) whereas no statistical difference among all groups was noted on 3 rd , 7 th and 14 th postoperative days.
In terms of postoperative inter incisal opening intra group comparison exerted no significant difference among all four groups, whereas inter group comparison between IM and control group on the first day after surgery; was proved to be statistically significant (p=0.044), however both IV and oral group seemed comparably efficacious in improving postoperative trismus when compared to control group but the result was statistically insignificant. However similar to the results of study by G. Koger et al 21 our study also showed no statistical difference among all corticosteroid groups on 3 rd , 7 th and 14 th postoperative days.
Chugh et al 22 suggested that probably steroids play a role in prevention of trismus. But it was because of the direct impact of steroid or was a result of reduction in swelling needs verification.
On 7 th day of surgery, swelling and trismus had back to baseline levels among all groups, indicating that the advantage of the medicine turned into at a maximum on initial 3 postoperative days. Our study also correlates as trismus and swelling almost returned to baseline on 7 th postoperative day in all four groups and the difference between them was statically insignificant.
All the groups were almost similar in their efficacy to reduce postoperative trismus on the 3 rd , 7 th and 14 th postoperative day, which could be attributed to administration of postoperative analgesic Tab Ketorol-DT for 5days in our study. As it has already been stated by Moore PA et al 98 in their study that trismus is partially associated with postoperative pain.

Pain
Postoperative pain and oedema are maximum around 48-72 h after surgery. The usage of corticosteroids to prevent postoperative pain is controversial. Some studies suggest that the swelling makes the tissue tense and ultimately causes tension pain, while reduced when swelling is reduced by the steroids (A. Chugh et al 23 ).
Actually Pain is a subjective sensation which can be influenced by plethora of factors like patient's anxiety age, gender, and surgical difficulty (Capuzzi P et al 23 ).
One study suggests the possibility of CS treatment to increase patient's reaction to pain, as a result of suppression of endorphin β levels. Koger et al 21 in his study using 20 mg of methylprednisolone neither measured nor compared pain probably due to subjective nature of pain sensation.
Vegas-Bustamante et al 18 evaluated the effect of a 40-mg injection of methylprednisolone within the masseter muscle considering oedema, trismus, and pain, following third molar surgery.They discovered that pain and swelling both were markedly reduced on 2 nd and 7 th postoperative days in study group with respect to control group. However, they concluded that pain being subjective in nature, an objective result should not be observed. Therefore they did not considered pain during the study (Vegas Bustamante 29 2008). Our results also show the same thing. Ustun et al 25 weighed the efficacy of 1.5 and 3 mg/kg of methylprednisolone via the i.v route and found that these doses were insufficient to afford significant pain reduction.
A study involving three groups of patients (control and the administration of 10 and 20 mg of prednisolone) presented insignificant differences in pain among the groups (Kang SH et al 26 ).
In our study, we observed statically significant mean difference in post op pain among all four groups (p=0.010). On first post op day, there was marked pain increase in control group whereas least pain was reported in IV group.
Intra-group comparison of mean pain score at 3 rd day was done between the groups. There was no significant difference in mean pain score between control, IM, IV and oral group (p=0.119) the result of our study was similar to results in study of Vaibhav et al 20 .
Intra-group comparison of mean pain score at day 7 th was also done. Although there was marked increase in pain reported by the patients of control group and least in IM group, there was no statistically significant difference in mean pain score between control , IM, IV and oral group (p=.270). Our results somewhat differed from results of Vaibhav et al 20 as the mean pain score was significantly different on 7 th postoperative day.
On 14 th post op day in our study, with respect to control group, all other groups proved to be better in terms of mean pain score while IM, IV and Oral group provided almost similar results (with a negligible difference of 0.08 on VAS score). It may be due to shorter half life as well as single dose of the drug.

Conclusion:-
Our study indicates that an intramassetric injection of methylprednisolone is most effective in reducing postoperative sequalae beacause it acts as a depot. Further studies with larger samples are needed to obtain more reliable results and to minimize these undesirable effects among patients.

Competing Interests
Author has no acknowledged conflicts of interest regarding this publication.