Use of Ibuprofen and Methylprednisolone for the Prevention of Pain and Swelling After Removal of Impacted Third Molars

J Oral Maxillofac Surg 53:2-7, 1995

Use of Ibuprofen and Methylprednisolone for the Prevention of Pain and Swelling

After Removal of Impacted Third Molars S. SCHULTZE-MOSGAU,* R. SCHMELZEISEN,1- J.C. FR(3LICH,::I::

AND H. SCHMELE,§

Purpose: To test a combination treatment of ibuprofen and methylpredniso- lone for pain and swelling.

Methods: The efficacy of 32 mg methylprednisolone on pain and swelling when given 12 hours before and after surgery in combination with 400 mg ibuprofen three times a day given immediately on the day of the operation and on the two subsequent days following removal of impacted third molars was investigated in a placebo-controlled, intraindividual double-blind study.

Results: After use of ibuprofen/methylprednisolone, ultrasonic examination showed a reduction in swelling of 56% (P < .001) compared with the placebo group; measurement with a tape measure showed a 58% (P < .001) reduction in swelling. The visual analog scale showed a reduction of 67.7% in postopera- tive pain in comparison with placebo.

Conclusion: The combination of ibuprofen and methylprednisolone has good analgesic and antiinflammatory action.

Dental procedures such as the surgical removal of impacted third molars produce tissue trauma that causes an infammatory reaction, v3 Cyclooxygenase and prostaglandins play a crucial role in the develop- ment of postoperative pain and swelling during such a react ionY Pain and swelling can be reduced via the membrane-stabilizing antiexudative effect of glucocor- ticoids and by inhibiting cyclooxygenase with nonste- roidal antiinflammatory drugs. 2'6 Thus, the postopera- tive administration of 40 mg methylprednisolone after surgical third molar removal led to a 46% reduction in swelling and a 50% reduction in pain. 7 The preoper- ative administration of 80 mg methylprednisolone be-

Received from the Institute of Clinical Pharmacology of Hannover Medical School, Hannover, Germany.

* Resident, Department of Oral and Maxillofacial Surgery. t Senior Consultant, Department of Oral and Maxillofacial Sur-

gery. ~: Head, Department of Clinical Pharmacology. § Fellow, Department of Oral and Maxillofacial Surgery. Address correspondence and reprint requests to Dr Schultze-Mos-

gau: Klinik und Poliklinik fur Mund-Kiefer-und Gesichtschirurgie, Medizinische Hochschule Hannover, Konstanty-Gutschow-Str. 8, 30625 Hannover, Germany.

© 1995 American Association of Oral and Maxillofacial Surgeons

0278-2391/95/5301-000253.00/0

fore Le Fort I osteotomy also produced a significant reduction in pain and swelling. 8 The administration of 6 mg dexamethasone after surgical third molar removal led to a 56% reduction in swelling compared with the placebo group. 9 Irreversible suppression of endoge- nous cortisol production can be largely excluded with such short-term administration. 1°

Various investigators who used nonsteroidal antiin- flammatory drugs for the prevention of pain after surgi- cal procedures demonstrated the superiority of 400 mg ibuprofen over 1,000 mg paracetamol, 11 650 mg acetyl- salicylic acid, 12'13 200 mg fendosal, 13 and 30 mg co- deine phosphate. 14 In one further study, perioperative medication with 400 mg ibuprofen produced a 64% reduction in pain. 15 Other investigators have also dem- onstrated the good analgesic efficacy of ibuprofen.16'17

Besides ultrasonography, alternative methods used to document soft tissue swellings are visual analog scales (VAS), photographs, stereo photographs, and f a c e - b o w s . 9'15Js'19 The disadvantage is that these meth- ods offer merely an indirect assessment of swelling on the skin surface. Using ultrasound, however, it is possible to assess directly the increase in the distance between the mucosa and the skin surface produced by the edema. Some investigators also regard computed tomographic documentation as an objective method of

SCHULTZE-MOSGAU ET AL 3

determining postoperative soft tissue swelling. 2° How- ever, this method is too complex and expensive for routine postoperative use to check the progress of swellings. Ultrasound can be used as a quick, noninva- sive, and time-saving method that does not affect the patient 's condition. It can also be used for the early diagnosis of hematoma or wound infection. 21

An intraindividual, placebo-controlled, double-blind study was performed to establish whether, the com- bined administration of ibuprofen and methylpredniso- lone is superior to their administration alone in the treatment of postoperative pain and swellings, and whether the combination of ibuprofen and methylpred- nisolone is a reliable form of medication to counteract postoperative pain and swelling after dental surgical procedures.

Materials and Methods

Forty healthy patients with four symmetrically im- pacted third molars underwent surgery as part of a prospective, intraindividual, randomized, double-blind crossover study. These were 33 females and 7 males with a mean age of 17.8 years (range, 13 to 26 years). The third molars of each patient showed orthograde impaction; root formation was not yet complete.

The teeth were removed in two sessions 6 weeks apart by one dental surgeon, as far as possible at the same time of day. At each session, the upper and lower teeth on the same side were removed. Articaine 4% with the addition of adrenaline 1:100,000 (Ultracain DS-forte, Bayer, Germany) was the local anesthetic used. The average quantity of local anesthetic adminis- tered was 3.1 mL. Analgesia was obtained in the lower jaw by nerve block anesthesia of the inferior alveolar nerve at the mandibular foramen and by infiltration anesthesia of the greater palatine nerve and terminal anesthesia of the posterior superior alveolar nerves. The teeth were removed by buccal osteotomy.

All patients received a combination of methylpred- nisolone and ibuprofen at either the first or second operation, in accordance with the randomization plan. At the other operation, a placebo of identical appear- ance was administered. The active medication con- sisted of 32 mg methylprednisolone (Urbason, Hoechst, Frankfurt am Main, Germany), which in each case was taken 12 hours before and after the operation (at about 8:00 PM on the day before the operation and at about 8:00 PM on the day of the operation), plus 400 mg ibuprofen (Tabalon, from Hoechst) which was given on the day of the operation, and on the first and second postoperative days, in each case at 8:00 AM, 1:00 PM, and 6:00 PM.

The placebo consisted of identical capsules con- taining lactose. As alternative medication for the treat- ment of severe pain occurring after the study medica-

FIGURE 1. Clinical determination of cheek swelling using a tape measure. Measurements are made of the distances from the lateral comer of the eye to the angle of the mandible (1), from the tragus to the outer comer of the mouth (2), and from the tragus to the progonion (3), preoperatively and on the first, third, and seventh postoperative days.

tion or the placebo had been taken, all patients were provided with codeine tablets (codeine phosphate 30 mg; Cascan, Wiesbaden, Germany) at both operations. The number of tablets used and the times they were taken were recorded.

Tape measurements and ultrasound examinations were performed on the first, third, and seventh postop- erative days to record the degree of swelling. 9 Cheek swelling was recorded clinically using a modification of the tape measure method described by Gabka and Matsumara. 22 Measurements were made of the dis- tances tragus-outer corner of the mouth, tragus-pogo- nion; and lateral corner of the eye-angle of the mandi- ble (Fig 1).

The course of the swelling was assessed ultrasoni- cally using a digital linear scanner (CS 9000; Picker, Munich, Germany) with a 5-mHz probe and a flexible polyvinylchloride block head (Sonokit, 3 D, Neuss, Germany; Fig 2), the concave surface of which was reproducibly connected to the side of the patient's swollen cheek. Cheek thickness was measured from the outer skin to the teeth in normal intercuspation.

4 IBUPROFEN AND METHYLPREDNISOLONE FOR THE PREVENTION OF PAIN AND SWELLING

FIGURE 2. The 5-mHz probe is placed on the flat surface of the polyvinyl chloride recording head. The concave 105 × 40-mm base area lies against the side of the patient' s cheek. Ultrasound gel was used to make an airtight connection.

placebo and then the active medication at the second operation. The main response variable was the reduc- tion in pain and swelling produced by the ibuprofen/ methylprednisolone medication compared with the control group. Carryover effects, period effects, and treatment/period interactions produced by the cross- over design were first checked using the Mann-Whit- ney U test; the measured values were used statistically only when there were no significant carryover or period effects. The significance level was set at P = .005. The data were evaluated using the SPSS software package (McGraw-Hill, Hamburg, Germany), 25 in collaboration with the Department of Biometry and Medical Com- puting, Hannover Medical School (Director: Professor Dr B. Schneider). The study protocol was examined and approved by the Ethics Committee of Hannover Medical School.

Results

The mean of three measurements was calculated. The marking points for the tape measurements and the ul- trasound measurements were drawn using a waterproof felt tip pen.

To assess the effect of the medication on the extent of postoperative trismus, maximal mouth opening was measured as the maximum bite width (MBW) preoper- atively and on the first, third, and seventh postoperative days. Postoperative pain was assessed clinically using a 10-cm long, horizontal visual analog scale (VAS), and a numerical scale (NS) marked 0 to 100. Pain was recorded on the VAS and the NS 1 hour after taking the medication (9:00 AM, 2:00 PM, and 9:00 PM) on the operation day, and on the first, second, third, and sev- enth postoperative days. Pain was assessed using the VAS and NS by adding together the three values for each day and comparing the totals.

Patients with partially impacted or displaced third molars, those with acute or chronic pericoronal in- flammation, or those with highly impacted teeth who were at increased risk of maxillary sinus perforation, were not included in the study. All patients in whom the operation time differed by more than 5 minutes between the two operations or who experienced post- operative bleeding or wound infection during the fol- low-up period were excluded from the study retrospec- tively. Also excluded were all patients who had taken drugs other than the study medication during the study period, who did not come for check-ups, and those who did not complete the case report form properly or in full.

The prospective investigation was designed statisti- cally as an intraindividual, randomized, double-blind c r o s s o v e r study. 23'24 Two groups were formed: group 1 received the active medication at the first operation, the placebo at the second; group 2 was first given the

Of the 40 patients, 14 were excluded from the study retrospectively. In four patients the difference between the operations was more than 5 minutes; six patients did not return or did not attend the follow-up examina- tions regularly; two patients had taken prohibited con- comitant medication.

Two patients (one on placebo and one on active drug) developed a wound infection on the first postop- erative day which needed draining. The data recorded for 26 patients (13 patients in group 1: medication/ placebo, and 13 patients in group 2: placebo/medica- tion) were thus available for evaluation. There were no period or carryover effects.

Preoperative tape measurements were 33.23 cm in the placebo and 33.04 in the experimental group, re- spectively. On the first postoperative day the patients who had taken the ibuprofen/methylprednisolone com- bination showed a mean value of 34.08 cm; the figure after placebo was 35.36 cm. On comparison of the differences between the placebo and the active medica- tion groups, a 58% reduction in swelling was found after medication (P < .001, Fig 3).

On the third postoperative day the sum of the tape measurements after active medication was 33.72 cm; the figure after placebo was 34.52 cm. The difference between active medication and placebo of 0.5 cm com- pared with the baseline value gave a reduction in swell- ing of 26.5% (P = .002).

Mean values of 22.15 m m (active medication group) and 22.05 mm (placebo group) were found preopera- tively using ultrasound. On the first postoperative day, cheek swelling of 25.35 m m was found after active medication and of 28.95 m m after placebo (Fig 4). With a difference of 3.46 mm, the reduction in swelling in the medication group was 56% (P < .001; Figs 5, 6). On the third postoperative day, ultrasound showed

SCHULTZE-MOSGAU ET AL 5

cm

37.00

36.00

35.00

34.00

33.00

32.00

Tape measurements

@ Ibuprofen/Methylprednisolon Placebo

8,5.36

preop 1. day 3. day 7. day

FIGURE 3. Graphs of tape measurements after the administration of ibuproferdmethylprednisolone and placebo. There is a significant reduction in swelling of 58% on the first postoperative day (1, P < .001; 2, P = .002).

values of 24.15 m m (active medication) and 26.30 mm (placebo). By comparison, the reduction in swelling produced by the combined medication was 22% (P = .001). In the active medication group there was a return to the preoperative baseline level (22.35 mm) on the seventh postoperative day. The difference of 1.2 m m after placebo compared with the baseline value corres- ponded to residual swelling (P < .001).

By contrast with the preoperative MBW of 49.75 m m (active medication) and 48.85 mm (placebo), on the first postoperative day a mean reduction in the MBW to 31.35 mm after medication was found and to 25.25 m m after placebo. The comparative increase in MBW of 5.2 mm after active medication was sig- nificant (P = .005). On the third postoperative day there were no significant differences in mouth opening (35.95 mm after active medication and 30.05 mm after placebo). On the seventh postoperative day the MBW was 41.25 m m in the active medication group and 36.75 mm in the placebo group. By comparison with the preoperative state, there was a significantly larger restriction of mouth opening of 3.8 m m after placebo (P = .042). There was no return to the baseline situa- tion, irrespective of the medication. After all opera- tions, mouth opening was still restricted on the seventh postoperative day. In the placebo group the restriction of mouth opening was 12.1 mm compared with the preoperative MBW; with ibuprofen/methylpredniso- lone medication, mouth opening was restricted by 8.5 m m (P = .003).

Evaluation of the VAS on the day of the operation showed a value of 48.5 mm with ibuproferdmethyl- prednisolone and 111.5 m m with placebo. On the first postoperative day, the mean ratings for patient pain were 43.5 m m after placebo and 11.5 m m after medica- tion. The difference of 32 m m on the VAS was signifi-

cant (P < .001). The values recorded on the second postoperative day were 23.5 mm after placebo and 13.5 m m after medication (P = not significant).

Evaluation of the NS showed a total reduction in pain after taking the ibuprofen/methylprednisolone combination of 75.5% on the day of the operation. On the first postoperative day pain in the placebo group was rated 28.0 m m higher (P = .000) on the NS. The difference between the combination medication and the placebo on the second postoperative day was 10.0 ram. No differences in pain intensity could be found on the third and seventh postoperative days.

After the administration of placebo, 23 codeine tab- lets were taken as alternative medication; only five codeine tablets were taken after the active medication. With 26 patients, this corresponds to a mean codeine tablet consumption of 0.9 after placebo and 0.2 after the active medication (P < .001).

After placebo, six patients experienced nausea or headaches, two patients had feelings of dizziness, and one patient had sleep disturbances; feelings of dizzi- ness occurred in one patient who had taken ibuproferd methylprednisolone. Subjectively, all patients believed that the postoperative period was less stressful after medication with ibuprofen and methylprednisolone.

Discussion

The administration of 32 mg methylprednisolone 12 hours preoperatively and postoperatively, combined with the postoperative administration of 400 mg ibu- profen on the day of the operation and the first 2 post- operative days, produced a clear reduction in postoper- ative pain and cheek swelling after impacted third molar removal. The intraindividual comparison dem-

mm

30.00

28.00

26.00

24.00

22.00

20.00

Sonographic measurements

• Ibuprofen/Methylprednisolon Placebo

2,,M.. W 22.35

22.05

preop 1.day &day 7. day

FIGURE 4. Graph of the ultrasound examination after combination medication and placebo. A reduction in swelling of 56% was found on the first postoperative day (1, P < .001; 2, P = .001).

6 IBUPROFEN AND METHYLPREDNISOLONE FOR THE PREVENTION OF PAIN AND SWELLING

FIGURE 5. A, The ultrasound measurement (5-mHz probe) from the skin surface of the cheek to the labial surfaces of the molar teeth in a 16-year-old woman before third molar re- moval (22 ram). B, measurement on the first postoperative day after taking placebo gave a value of 30 ram.

onstrated the efficacy of this combination medication compared to placebo.

The total reduction in swelling on the first postopera- tive day compared with the placebo group was 56% on ultrasound measurement and 58% when measured with a tape. The differences found on the third postop- erative day corresponded to a reduction in swelling after medication o f 26.5% on tape measurement and 22.0% using ultrasound. The restriction of mouth open- ing was reduced by 28.8% on the first postoperative day. These differences are of clinical significance as can be seen by the concomitant reduction in the con- sumption of codeine.

The reduction in pain on the day of the operation after the administration o f ibuprofen/methylpredniso- lone was 67.7% (VAS) or 75.7% (NS). The differences found on the first and second postoperative days using both scales likewise corresponded to significant reduc- tions in pain when ibuprofen/methylprednisolone was taken.

The administration of methylprednisolone alone in orthodontic operations has produced a significant re- duction in swelling. 2° In another placebo-controlled study, a single preoperative intravenous administration o f 125 mg methylprednisolone led to a significant re- duction in pain and swelling after third molar re- moval. 26 The preoperative intramuscular administra- tion of 80 mg methylprednisolone led to a reduction in the incidence of wound edema from 88.6% to 61.4% after the removal o f impacted third molars. 8

Two earlier studies investigated the reduction in pain and swelling after third molar removal by the adminis- tration of 6 mg dexamethasone alone or by the adminis- tration of 400 mg ibuprofen alone. 9'15 The administra- tion of 6 mg dexamethasone alone led to a reduction in swelling of 28% (ultrasound) and 58% (tape mea- sure) on the first postoperative day, and to a reduction in trismus of 17%. 9 When 400 mg ibuprofen was ad- ministered alone on 3 successive days, a 64% reduction in pain was found but ultrasonically significant reduc-

FIGURE 6. A, Ultrasound measurement (5 mHz) of cheek swelling in a healthy 18-year- old woman preoperatively and (B) on the first postoperative day after third molar removal under medication with methylprednis- olone perioperatively and ibu- profen postoperatively. A value of 19 mm was found preopera- tively and 22 mm on the first postoperative day.

KENNETH M. HARGREAVES 7

tion in swell ing was found.15 The results of the present

study show that the combinat ion of ibuprofen and

methylprednisolone has a better analgesic and antiin-

flammatory action than the administrat ion of a gluco- corticoid or a nonsteroidal anti inflammatory alone. Other studies have also demonstrated that the action is potentiated when the two drugs are administered in combination. 27'28 The combinat ion of ibuprofen and

methylprednisolone is therefore well suited to the treat-

ment of postoperative pain and swelling after dental surgical procedures, and should be used when exten- sive postoperative swelling of soft tissue is expected.

The good agreement between the tape measurements

and the results of the ul trasound follow-up examina-

tions proves the suitability of ul trasound as a means

of objectively assessing postoperative soft tissue swell- ing. This is also demonstrated by the results of other studies. 9,21

References

1. Dieckmann J: M6glichkeiten der Schmerzverringerung durch Odemprophylaxe und Ausschaltung k6pereigener schmerer- zeugender Substanzen. Fortschr Med 96:1475, 1978

2. Hotz G: Medikament6se Behandlung postoperativer und post- traumatischer SchwellungszustS.nde. ZWR 3:256, 1986

3. Little RC, Ginsburg JM: The physiologic basis for clinical edema. Arch Intern Med 144:1661, 1984

4. Riede UN: Entztindungspathologie, in Riede UN, Schiifer HE, Wehner H (eds): Allgemeine und spezielle Pathologie. Stutt- gart, Germany Georg Thieme Verlag, 1989

5. Zimmermann M: Basic concepts of pain and pain therapy. Drug Res 34:1053, 1984

6. Blackwell GJ, Carnuccio R: Macrocortin: A polypeptide causing the antiphospholipase effect of glucocorticoids. Nature 287:147, 1980

7. Skjelbred P, L6kken P: Effects of naloxone on postoperative pain and steroid-induced analgesia. Br J Clin Pharmacol 15:221, 1983

8. Nordstr6m REA, Nordstr6m RM: The effect of corticosteroids on postoperative edema. Plast Reconstr Surg 7:85, 1987

9. Schmelzeisen R, Fr/51ich J: Prevention of postoperative swelling and pain by dexamethasone after operative removal of im- pacted third molar teeth. Eur J Clin Pharmacol 44:275, 1993

10. Montgomery MT, Hogg JD, Roberts DL, et al: The use of glucocorticosteroids to lessen the inflammatory sequelae fop

lowing third molar surgery. J Oral Maxillofac Surg 48:179, 1990

11. Beaver WT, Forbes JA, Barkazi BA: An evaluation of ibuprofen and acetaminophen in postoperative oral surgery. Cliu Phar- macol Ther 41:180, 1987

12. Brogden RN: Non-steroidal anti-inflammatory analgesics other than salicylates. Drugs 32:27, 1986

13. Forbes JA, Barkaszi BA, Ragland RN, et al: Analgesic effect of fendosal, ibuprofen and aspirin in postoperative oral sur- gery pain. Pharmacotherapy 4:385, 1984

14. Frame JW, Evans CRH, Flaum GR, et al: A comparison of ibuprofen and dihydrocodeine in relieving pain following wisdom teeth removal. Br Dent J 166:121, 1989

15. Schmelzeisen R, Buchweitz IK, Fricke A, et al: Medikament6se analgetische Kombinationsbehandlung nach Weisheitszah- nosteotomien mit Ibuprofen. Dtsch Z Mund Kiefer Ge- sichtsChir 14:442, 1990

16. Billigmann PW: Vertr/~glichkeit yon lbuprofen. Fortschr Med 109:213, 1991

17. Brown P, Mehlisch D, Block E, et al: The comparativ e effective- ness of ibuprofen 200 mg, acetaminophen 650 mg and pla- cebo in postextraction dental pain. J Clin Pharmacol 31:856, 1991

18. Berge IT: Visual analogue scale assessment of postoperative swelling. Acta Odontol Scand 46:233, 1988

19. Breytenbach HS: Objective measurement of post-operative swelling. Int J Oral Surg 7:386, 1978

20. Schaberg S J, Stuller CB, Edwards SM: Effect of methylprednis- olone on swelling after orthognatic surgery. J Oral Maxitlofac Surg 42:356, 1984

21. Knopp W, Muhr G, Josten C, et al: Ultraschalldiagnostik postop- erativer H/imatome. Unfallchirug 89:293, 1986

22. Gabka J, Matsumara T: Me/3technische und klinische Prfifung eines Antiphlogistikums (tantum). Munch Med Wochenschr 13:198, 1971

23. Hecker H: Identification and interpretation of effects in two- period crossover designs, in EDV in Medizin und Biologie, Vol 17. Stuttgart, Germany, Gustav Fischer Verlag, pp 60- 66

24. Schneider B: Crossover designs and repeated measurements. Neuropsychobiology 10:49, 1983

25. Schuboe W, Uehlinger HM: Handbuch der Programmversion 2 SPSS X. Stuttgart, Germany, Gustav Fischer Verlag, 1984

26. Beirne OR, Hollander B: The effect of methylprednisolone on pain, trismns and swelling after removal of third molars. Oral Surg Oral Med Oral Pathol 61:134, 1986

27. SiskAL, Bonnington GJ: Evaluation ofmethylprednisolone and flurbiprofen for inhibition of the postoperative inflammatory response. Oral Surg Oral Med Oral Pathol 60:137, 1985

28. Troullos ES, Hargraves KM, Butler DP, et al: Comparison of nonsteroidal and anti-inflammatory drugs, ibuprofen and flurbiprofen, with methylprednisolone and placebo for acute pain, swelling and trismus. Int J Oral Maxillofac Surg 48:945, 1990

d Oral Maxillofac Surg 53:7-8, 1995

Discussion Use of Ibuprofen and Methylprednisolone for

the Prevention of Pain and Swelling After Removal of Impacted Thrid Molars

Kenneth M. Hargreaves, DDS, PHD Minneapolis, MN

This study provides additional support for the finding that nonsteroidal antiinflammatory drugs (NSAIDs) and gluco-

corticoids reduce the development of postoperative pain and inflammation. The magnitude of the analgesic and antiin- flammatory effect is similar to that observed in previous studies.] In general, studies have indicated that NSAIDs have relatively greater analgesic and less antiinflammatory activ- ity than glucocorticoidsJ Comparatively few studies have evaluated the activity of combinations of the two drugs.

Some modification of the authors' conclusions should be considered. This study does not demonstrate that the combi- nation of the two drugs is superior to either agent alone. The