Europ.J.clin.Pharmacol. © Springer-Verlag 1975

8, 209-216

(1975)

Bilateral Surgical Removal of Impacted Lower Third Molar Teeth as a Model for Drug Evaluation: A Test with Ibuprofen P. LSkken,

I. Olsen, I. Bruaset and K. Norman-Pedersen

Institute of Pharmacology and Department of Oral Surgery and Oral Medicine, Received:

July 31, 1974,

accepted:

University of Oslo, Norway

September 23, 1974

Summary. It was considered that double-blind crossover studies of therapeutic efficacy after acute injury could well be done in patients who required surgical removal of impacted wisdom teeth from both sides of the lower jaw. In the present trial 24 healthy patients received either placebo or ibuprofen (Brufen@: 400 mgthree times daily), a non-steroidal anti-inflammatory agent, for 5 days commencing the day before surgery. Treatments were given on the two occasions when impacted wisdom teeth were to be removed from one side or other of the lower jaw. A number of objective and subjective parameters were recorded for paired comparison of the post-operative courses, including swelling, trismus and pain. A mechanical device which allows simple and accurate measurement of cheek swelling is described. On the ist, 3rd and 5th post-operative days in the ibuprofen group the measured swelling averaged 93, 89 and-82%, respectively, of that in the placebo group; the corresponding o-values were 0.35, 0.06 and 0.07. Patients with less swelling after ibuprofen were not always those with a high serum concentration of the drug. Ibuprofen significantly reduced pain on the day of the operation. This may at least partly account for less trismus and the preference of the patients for their postoperative courses with ibuprofen. Examination of various haematological parameters did not reveal any significant difference between the two operations. Subjective scores indicated that neither woundhealing nor bleeding was affected by ibuprofen, nor were any side effects detected.

Key words: Anti-inflammatory

effects,

oedema measurements,

There is a lack of reliable methods for clinical assessment of anti-inflammatory effects, The aim of the present work was to establish a model in which the pharmacological effects of anti-inflammatory drugs could be evaluated by their ability to modify the post-operative course. Patients who required prophylactic removal of "identical", bilaterally impacted mandibular third molars were studied. They represent a unique material, as essentially the same operation is performed twice on healthy asymptomatic individuals, who can serve, therefore, as their own controls. The experimental design was on a double-blind crossover basis. It required development of a new method for quantitative measurement of post-operative swelling in the facial region.

Material and Methods Patients The study comprised 24 healthy out-patients, 15 females and 9 males (mean age 20 years, range 16-

ibuprofen,

oral surgery, double-blind

trial.

28), who volunteered to participate after explanation of the implications of the trial. Selection was based upon orthopantomographic radiographs (Fig. I). The criteria of acceptance were asymptomatic, non-erupted lower third molars of similar depth and position, which were considered equally difficult to remove. Medication The randomization system ensured that half of the patients received the active drug at the first operation. The distribution of placebo and ibnprofen at the operation on each side was also the same, since righthanded surgeons may operate more efficiently on the right side of the mouth. Medication started on the day prior to surgery and continued for a total of 5 days, either with ibuprofen (Brufen®) or a matching placebo tablet, followed by crossover to the alternative treatment at the second operation. The daily dose of ibuprofen was 1.2 g, divided into 3 single doses taken

210

Fig. i. Orthopantomogram of bilateral non-erupted third molars in similar positions

at 8 a.m., 3 p.m. and i0 p.m.. No other drugs were taken during the trial. Operations All operations were done on Fridays by the same surgeon and assistant; the mean interval between operations was 26 days (range 21-35 d). Efforts were made to employ exactly the same technique at both operations. The mean duration from incision to last suture at the operations on the ibuprofen group was 15.5 min (range 3-40), compared to 14.5 min (range 5-37) in patients who received the placebo. The average quantity of local anaesthetic (Xylocain-Exadrin R 'Astra' 2%) was 3.1 ml (range 1.9-8.1) when ibuprofen was given, and the corresponding value for the placebo was 3.2 ml (range 1.9-5.4). Swelling

Fig. 2. Device for measurement of swelling in the jaw region

To obtain a reliable and accurate measurement of cheek swelling, the device shown in Fig. 2 was constructed. It consists of 16 adjustable plastic screws (8 on each side) on bilateral plates, which are fixed on a facial bow attached to an individual bite-block. Since it was necessary every time to be able to insert, remove and reinsert the instrument in exactly the same position in relation to the skull, the bite-block was an essential part of the device. At the first pre-operative examination it was obtained by taking a thermoplastic impression (Paribar ~, Amalgamated Dental Trade Distributors Ltd., London, England) of the patient's dentition in occlusion. When the plastic screws were adjusted into touch contact with the skin, measurement of the remaining length of the 8 screws outside the plate would give the examiner exact values, which could easily be related to the degree of facial swelling by simple subtraction of post- and pre-

211

Bleeding

operative measurements. At each sitting, two parallel measurements were performed, between which the screws were adjusted to zero position. Their mean value was used as the final result. The standard deviation calculated for the 48 parallel sets of pre-operative measurements was as low as ±0.036 mm. Since both swelling and various degrees of contraction of the muscles could change the contour of the delimited area, it was important to keep the head of the patient in the same position at each measurement. At all the post-operative examinations, before and independent of the quantitative measurements, the swelling was graded according to the examiner's subjective impression as none, slight, moderate or marked.

The tendency to bleeding was graded by the surgeon during the operations and by the patients on the five consecutive days as none, slight, moderate, or severe. Wound-Healing Wound-healing was assessed on the fifth postoperative day, using terms and criteria according to Khosla and Gough (|). Haematological Examination Two days before and five days after each operation blood samples were obtained for estimation of erythrocytes, haemoglobin, haematocrit, ESR, platelets and white blood count.

Mouth-opening Two days before and on the first, third and fifth day after surgery, the ability to open the mouth was determined. A vernier gauge was used to measure the distance between the edges of the upper and lower central incisors. Three consecutive readings were recorded with the mouth open as far as possible, and their mean taken as the final result. Postoperative mouth-opening ability was expressed as a percentage of the pre-operative measurement.

Serum Concentration of Ibuprofen Blood samples for measurem4nt of the serum concentration of ibuprofen were taken immediately after each operation and on the first post-operative day. Serum was separated and stored frozen. At the end of the trial, samples obtained during treatment with ibuprofen were sent to the Research Dept. of The Boots Co. Ltd., Nottingham, England, for assay.

Pain Patients were asked to assess post-operative pain in terms of five grades: nil, mild, moderate, severe, or very severe. A printed sheet was provided and each patient was instructed to record the degree of pain present according to these five grades, just before bedtime on the day of operation and at the same time on the five following days.

SWELLING 1st post- operative day

Side effects Side effects were inquired about at each examination with the following standard question 'Have you experienced any discomfort which can possibly be ascribed to the medication?' In addition, patients were asked about the symptoms recorded in Table 3.

- PAIRED

COMPARISON

3 rd post -operative day

100rnm

I B U P R O F E N

5th post-operative day ! 00mm

80-

80o

60•

•

•

o 0

60-

o

40-

/.0-

80-

< • o

0

20-

20-

•

I

I

I

I

20

40

60

80

I

100mm 0

•

0

60•oO

40-

0

oe °

20-

I

I

I

I

20

40

60

80

l

100mm 0

I

I

I

I

20

40

60

80

I

lOOmm

PLACEBO • ibuprofen,oplacebogiven at the 1st operation

Fig. 3. Measured post-operative swelling after surgical removal of bilaterally impacted lower third molars, in a crossover trial of 24 patients receiving ibuprofen and placebo. Each point represents one patient and the total swelling recorded by 8 bilateral measuring pins. Patients with more swelling after the operation when the placebo was given are shown below the diagonal line, and those with more swelling after ibuprofen are shown above it

212

The patients' preference about the post-operative course was asked about on the first, third and fifth day after the second operation. They were then asked to give an overall assessment of the course after this operation compared to their previous experience, according to the rating: better, no difference or worse.

Mouth-Opening Individual values are illustrated in Fig. 5. When ibuprofen had been given, the average mouth-opening capacity was reduced to 81.8, 86.4 and 86.5% on the first, third and fifth post-operative days, respectively, compared to 72.5, 76.9 and 82.1% with placebo. A one-tailed paired comparison in the Wilcoxon test gave corresponding a-values of 0.02, 0.01 and O.18.

Results Pain Swelling

On the day of surgery, 18 of the 24 patients reported less pain when ibuprofen had been given, and only 2 reported less pain with placebo (Fig.6). Statistical analysis according to the binomial theorem showed that the difference was significant, p = 0.02. Analysis of pain scores on the following days did not reveal any significant differences (p > 0.05). On no occasion did any patient report pain as 'very severe'.

On the first post-operative day, when ibuprofen had been given, the total swelling measured in 24 patients was 93.3% of that with placebo (899.3 v. vs. 964.2 mm). According to a one-tailed paired comparison in the Wilcoxon test (a = 0.34), this difference is not significant. In fact, 12 of the 24 patients had more swelling when receiving ibuprofen (Fig. 3). On the third post-operative day the swelling in ibuprofen-treated patients was 88.6% of that with placebo (717.1 vs. 809.3 mm; ~ = 0.06). On the fifth post-operative day the swelling in ibuprofen-treated patients was 81.7% of that with placebo (375.2 vs, 459.3 mm; a = 0.O7). When the code was broken and the subjective assessments were related to the measured values, each subjective score was found to cover a broad, overlapping field of measured values (Fig. 4).

Bleeding Subjective assessment did not reveal any clinically apparent effect of ibuprofen on the bleeding tendency, either during or after the operation (Table I). Wound-Healing Wound-healing did not seem to have been affected by ibuprofen (Table 2).

SUBJECIIVE SCORES oo

MARKED

•

Q MODERATE

--

SLIOHT

-

•

•

|e

~

NONE

ee

oe,ee

o

. •

eeoe

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,.. ~ ' ~ . . ' ;

|

I

I

I

I

I

I

10

20

30

40

50

60

I

1

I

?0

80

90

I

100 mm

MEASURED VALUES

Fig. 4. Relationship between clinical assessment of swelling and measured values. Each measured value is the total of the measurements with 8 measuring pins in the region of swelling

2]3

PER CENT OF PRE - OPERATIVE t st post- operative day

°°o, ..o/:

100% I B

80- .

o

" o" t

3rd post-operative day o o

80-

"o .#. •

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o

o

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5th post-operative day

o

./;:o"

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/,0-

/.0-

/.0-

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°

o

PAIRED COMPARISON

60-

60-

t

/o /

-

60-

U P

~

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,oo_

MOUTH- OPENING

R

N

I

20

l

I

/.0 60 PLACEBO

I

80

I

100%

0

!

I

I

I

20

40

60

80

I

100%

0

I

I

I

I

20

/.0

60

80

I

100%

• ibuprofen,oplacebo given at the tst operation

Fig. 5. Percentage of pre-operative mouth-opening ability after surgical removal of bilaterally impacted lower third molars in 24 patients receiving ibuprofen and placebo. Patients with greater ability to open the mouth after the operation when ibuprofen was given are shown above the diagonal line, and those with greater ability after placebo are shown below it PAIN I B U

Strong

P R 0

Moderate

F

Shght

E N

SCORES - PAIRED

Day of operation

COMPARISON

1st post-operative day

Haematolo~ical

Findings

After surgery with ibuprofen, none of the changes in the haematological parameters differed significantly from those found after the placebo (Table 3). Serum Concentration

None

SI =ght Moderate Strong • .buprofen, o placebo g~ven PLACEBO at thelst operat.on 2nd post-operat ive day 3rd post-operat ire day

of Ibuprofen

Serum analyses confirmed ibuprofen intake in all patients. On the first post-operative day, 3 h 58 min ± 3 min after the seventh dose (0.4 g) of ibuprofen was to have been taken, the serum concentration was 16.9 ± ].5 ~g/ml (mean ± SE). As shown in Fig. 7, after surgery with ibuprofen there did not appear to be any trend towards less swelling in subjects with higher serum concentrations. Also, the level of ibuprofen in samples taken immediately after surgery did not show any clear correlation with the degree of swelling Side Effects

!

!

I

/. th post-operative day

I

I

I

5th post-operative day

Side effects were all mild and the incidence of complaints low both with ibuprofen and placebo (Table 4). In addition to the side effects specifically asked for, two patients reported fatigue one after the placebo and the other after both placebo and ibuprofen. Preference

!

!

t

Fig. 6. Effect of ibuprofen and placebo on subjective impressions of pain after surgical removal of bilaterally impacted lower third molars. Patients with more pain after the operation with placebo are shown below the diagonal line, and those with more pain when ibuprofen was given are shown above it

On the first day after the second operation, 75% of the patients preferred the post-operative course with ibuprofen, while 21% preferred placebo (Table 5). On the third and fifth day after surgery, the number of patients who favoured ibuprofen was reduced, and an increasing number reported no difference.

Discussion Prophylactic removal of impacted third molars in young patients is generally recommended, even if

214 the teeth are symptomless (2,3). The operative procedure is often associated with quite strong inflammatory reactions including swelling, trismus and pain. A number of steroidal and non-steroidal drugs have been reported previously to reduce the incidence and severity of sequelae after oral surgery (4-13). In the present model, the same surgical procedure was performed twice on healthy asymptomatic patients with bilaterally impacted lower third molars. Thus, variation due to individual differences and spontaneous fluctuation in disease activity should have been eliminated or minimisad. Several methods have been employed to assess swelling following surgery to the jaws, clinical rating (e.g. 4,5,10,12,14,15), mechanical methods (e.g. 7,8,11,13,16-19), contrast radiography (20,21), stereometry or measurements on photographs (6,9,22,23). The device constructed for the present study permitted simple, accurate and reproducible measurement of the swelling. It may therefore offer advantages compared to the methods employed previously. Clinical assessment of swelling is simple and is in common use, but, according to the present findings, it is neither accurate nor reliable. In all cases the main swelling was found within the area covered by the pins. Aithough the swelling sometimes was minimal, none of the postoperative measurements on any patient gave a negative value for it. Ibuprofen is a non-steroidal agent, which may be up to 32 times more potent in animals than acetylsalicylic acid with respect to anti-inflammatory, analgesic and antipyretic activities (24).

Table I. Bleeding tendency after surgical removal of lower third molars after placebo (P) or ibuprofen (I) Bleeding score

During° a Day of. b operatlon operatlon

Days afte[ operation ~ I 3 5

P

I

P

I

P

None

-

-

3

2

22 20 24 21 21 22

Slight

15

17

19

18

2

3

9

7

2

4

-

1

Moderate Severe

.

.

.

I

P

I

-

P

3

I

3

.

a

Assessment by the oral surgeon b

Assessment by the patient

Table 2. Wound-healing on the fifth post-operative day after surgical removal of lower third molars in placebo and ibuprofen groups Healing

Medication

by

Placebo

First intention

Ibuprofen

16

16

Second intention

7

6

Third intention

1

2

Table 3. Haematological findings in a double-blind crossover study of surgical removal of lower third molars in 24 patients who received placebo and ibuprofen Paired comparison of the difference between the changes (Wilcoxon)

Mean values 2 days before and 5 days after the operations Placebo Parameter

Before

Ibuprofen After

Change

Before

After

Change

Erythrocytes 106/mm 3

4.83

4.78

-0.05

4.80

4.71

-0.09

0.42

Haemoglobin g/lO0 ml

14.49

14.23

-0.26

14.52

14.25

-0.27

0.49

Haematocrite %

42.83

42.25

-0.58

43.13

42.58

-0.54

0.46

E.S.R. mm/h

5.6

8.8

3.2

5.6

10.6

5.0

0.17

Platelets 106/mm 3

3.86

3.52

-0.35

-0.23

0.34

3.78

3.55

White blood cells/mm 3

4750

5288

537

4829

5171

342

0.31

% Neutrophils

55.7

58.6

2.9

54.8

59.9

5.1

0.12

% Eosinophils

1.6

1.9

0.3

1.5

1.9

0.4

0.50

% Basophils

0.4

0.5

O.i

0.4

0.4

0.0

O.21

% Monocytes

4.2

4.6

0.4

4.2

4.9

0.7

0.28

38.0

34.1

-3.9

39.0

32.8

-6.2

0.18

% Lymphocytes

2

215 Table 4. Numbers of reported side effects after surgical removal of lower third molars in 24 patients receiving placebo and ibuprofen Placebo Asked for

.ug ibu~rofen ml serum

I.

Ibuprofen

Day of Days Day of operation after operation operation I 3 5

Days after operation I 3 5

1° .

20

•

Headache

0

2

2

I

0

I

I

2

Vertigo

0

1

0

0

1

i

I

0

Nausea

1

I

1

i

0

I

I

i

Abdominal pain

0

0

i

I

0

0

0

0

Dyspepsia

0

0

2

0

2

0

i

0

•

•

Table 5. Preference for post-operative course stated after second operation in a doubleblind crossover study of surgical removal of lower third molars in 24 patients receiving placebo and ibuprofen Placebo better

Ibuprofen better

No difference

No.

No.

No.

%

%

%

i

5

21

18

75

I

4

3

6

25

12

50

6

25

5

6

25

9

37

9

37

The drug has been shown to be well tolerated and an effective analgesic in the treatment of rheumatoid arthritis and osteoarthrosis. There is some divergence of opinion about its anti-inflammatory effect in man (25-28). It has been argued that the methods of measurement of inflammation in man are too crude to demonstrate anti-inflammatory effects of drugs such as ibuprofen (29). Clinical trials with ibuprofen have mainly been performed in patients suffering from rheumatic complaints, but it has been reported of value in sport injuries (30,31). In the present model its ability to suppress pain and inflammation associated with acute injury was tested. The drug was well tolerated. On the day of surgery ibuprofen reduced pain. This may, at least in part, account for the reduction in trismus and the patients' preference for ibuprofen. Its capacity to suppress post-operative swelling was not very impressive. The authors are grateful to The Boots Co., Ltd., Research Dept., Nottingham, England, for assistance and supply of drugs.

•

10

•

I

I •

100

50

Per cent less swelling with placebo

J

I

I

0

50

100

Per cent less swelling w i t h ibuprofen

Fig. 7. Relationship between serum concentration of ibuprofen and swelling on the first postoperative day in a double-blind crossover trial with 24 patients who received placebo and ibuprofen. On the left side of the vertical axis are the patients who had less swelling whilst receiving the placebo, and on the right side are those with less swelling when ibuprofen was given. Values are the percentage of the swelling when the alternative treatment was given

References i.

2.

3.

4.

5.

6.

Acknowledgement.

•

eJ O

I

Days after operation

•

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216

7.

Fleuchaus, P.T.: Effect of hyaluronidase on swelling and trismus after removal of impacted mandibular third molar teeth. Oral Surg. 9, 493-500 (1956) 8. Hahn, W., Lange, D., Overheu, M.: Die Vermeidung des postoperativen Odems. Dtsch. Zahn~rztebl. 20, 355-360 (1966) 9. Holley, J.R., Francis, F.H.: Betamethasone in traumatic oral surgery. J. oral Surg. 27, 398403 (1969) i0. LaDow, C.S., Henefer, E.P.: Indomethacin, a new anti-inflammatory agent: A preliminary report. J. oral Surg. 24, 253-255 (1966) II. Linenberg, W.B., Westfield, N.J.: The clinical evaluation of dexamethasone in oral surgery. Oral Surg. 20, 6-28 (1965) 12. Nathanson, N.R.. Seifert~ D.M.: Betamethasone in dentistry. Oral Surg. 18, 715-721 (1964) 13. Rao, B.C., Khera, S.S.: Indomethacin in oral surgery. J. Indiana dent, Ass. 44, 78-80 (1972) 14. Husted, E., HjSrting-Hansen, E.: The effect of G.27202 (Tanderil ®, Geigy) on post-operative discomfort following removal of the lower third molar. Acta odont, scand. 20, 205-213 (1962) 15. Szmyd, L., Shannon, I.L., Mohnac, A.M.: Control of postoperative sequelae in impacted third molar surgery. J. oral Ther. Pharmacol. I, 491-496 (1965) 16. M~ller, J.F., Buch, N.H.: Chymar som adjuvans ved operativ fjernelse af visdomstaender. Ugeskr. Laeg. 126, 851-853 (1964) 17. Ritzau, M.: M$1ing af haevelse efter fjernelse af visdomstaender i underkaeben. Tandlaegebladet 76, 452-460 (1972) 18. Sowray, J.H.: An assessment of the value of lyophilised chymotrypsin in the reduction of post-operative swelling. Brit. dent. J. 110, 130-133 (1961) ]9. ~gren, E.: High-speed or conventional dental engines for the removal of bone in oral surgery. Acta odont, scand. 21, 585-625 (1963) 20. Forman, G.H.: A radiographic method of assessing post-operative swelling. Brit. dent. J. 117, 149-152 (1964) 21. Forsberg, A.: RSntgenologisk registrering av mjukdelssvullnad. Sverig. Tandlgk.-FSrb.Tidn. 49, 165-173 (1957) 22. Antonioli, C.A., Held, A.-J.: Evaluation clinique d'un mSdicament antiphlogistique

23.

24.

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26.

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28.

29.

30.

31.

("Tantum") apr~s mise au point d'un module exp&rimental. Schweiz. Mschr. Zahnheilk. 82, 473-499 (1972) BjSrn, H., Lundquist, C., HjelmstrSm, R.: A photogrammetric method of measuring the volume of facial swellings. J. dent. Res. 33, 295-308 (1954) Adams, S.S., McGullough, K.F., Nicholson, J. S.: The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch. Int. Pharmacodyn. 178, 115-129 (1969) Davies, E.F., Avery,~G.S.: Ibuprofen: a review of its pharmacological properties and therapeutic efficacy in rheumatic disorders. Drugs 2, 416-446 (1971) Deodhar, S.D., Dick, W.C., Hodgkinson, R., Buchanan, W.W.: Measurememt of clinical response to anti-inflammatory drug therapy in rheumatoid arthritis. Quart. J. Med. (N.S.) 42, 387-401 (1973) Huskisson, E.C., Hart, F.D., Shenfield, G.M., Taylor, R.T.: Ibuprofen. A review. Practitioner 207, 639-643 (1971) Pavelka, K., Susta, A., Vojtisek, Br~mov~, A., Kankov~, D., HSndlov~, D., Malecek, J.: Doubleblind comparison of ibuprofen and phenylbutazone in a short-term treatment of rheumatoid arthritis. Arzneimittel-Forsch. 23, 842846 (1973) Huskisson, E.C., Wojtulewski, J.A., Berry, H., Scott, J., Hart, F.D., Balme, H.W.: Treatment of rheumatoid arthritis with fenoprofen: comparison with aspirin. Brit. med. J. 1974 I, 176-180 Nilsson, S., Husby, G., Roaas, A.: Ibuprofen in the treatment of sport injuries. Excerpta med., Int. Congr. Ser. No.299 (1973) p. 157 (Abstr. No. 542.) Vrillac, M., Barrau, J., Molin~, J.: Traitement anti-inflammatoire par l'ibuprofen en pathologie sportive. Soc. Med. Chir. Hop. 5, 31-34 (1973)

Dr. P. L~kken Institute of Pharmacology Univ. of Oslo Oslo, Blindern Norway