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The lower third molar and antiphlogistics
Int. J. Oral Surg, 1982: 11: 340-350
Review article
(Keywords: molar, lower third; removal a/molar; antiphlcgistics : trismus: pain)
The lower third molar and antiphlogistics Effects of betamethasone, ibuprofen, indomethacin, naproxen, niflumic acid, oxyphenylbutazone, tranexamic acid and glafenine on the patient's condition after surgical removal of a lower third molar J. VAN DER ZWAN, G. BOERING, H. WESSELING, C. TH. SMIT SIBINGA AND L. TH. VAN DER WEELE
DepartmentsofOral Surgery, and Internal Medicine, University Hospital ..Department ofClinical Pharmacology, Mathematical Center, State University, Groningen, The Netherlands
ABSTRACT - A multidisciplinary, double blind, parallel placebo controlled investigation was made to find an effective anti-inflammatory drug which prevents postoperative swelling, trismus and a general feeling of malaise. An additional aim was to evaluate objectively the anti-inflammatory properties of anti-rheumatics. In 126 healthy patients, who were without complaints, the lower third molar was surgically removed. A drug had to be taken orally according to a fixed scheme for 4 days. Glafenine had to be taken in case of pain. The number of tablets taken was used to quantify pain. Swelling of the cheek was measured photographically and trismus was deducible from the maximal mouth-opening. The drugs investigated were betamethasone 14.5 mg decreasing over 4 days, ibuprofen 1200 mg/day, indomethacin 150 mg/day, naproxen 750 mg/day, niflumic acid 1000mg/day, oxyphenylbutazone 600 mg/day and tranexamic acid 2000 mg/day. Oxyphenylbutazone and tranexamic acid were not significantly different from placebo in their pain-killing effects. Betamethasone prevents swelling and trismus significantly more than the placebo. Betamethasone is significantly better than the other drugs in the prevention of swelling. Reduction of the swelling by anti-rheumatics may be 10-15% and a 20% reduction of trismus is to be expected. The strongest analgesic is niflumic acid. Tranexamic acid may perhaps reduce the swelling by 28%. The questionnaire and the blood- and urine-test Showed that anti-rheumatics have to be considered to be acetylsalicylic acid-like drugs. Serious side effects have been reported previously for anti-rheumatics. When taken for a short time, corticosteroids are very safe drugs with a few mild side-effects. Many patients experience a slight euphoria. Betamethasone, in a dosage of 14.5 mg decreasingly divided over 4 days prevents pain by 80%, swelling by 65% and trismus by 40% compared with the placebo group. This safe drug is recommended in elective surgery.
0300-0785/82/060340-11$02.50/0 © 1982 Munksgaard, Copenhagen
ORAL SURGERY AND ANTIPHLOGISTICS
Counteracting post-operative complaints after surgical removal of the wisdom-tooth from the lower jaw has already been the subject of research many times. VAN GOOL I 2 was able to establish that pain, swelling and trismus were reduced by: making a vertical relaxing incision; little use offorce for the removal of the tooth; no plug in the alveolus; no primary closing of the wound; short duration of the operation. The development of post-surgical swelling and trismus and malaise remains a problem in spite of application of the principles mentioned. A good and safe antiphlogistic drug is clearly still needed. A complete literature survey of their applications in oral surgery is to be found as part of a thesis". The literature concerning side effects can be found completely brought up to date in several reference books, e.g, Meyler's side effects of drugs", with its annual supplements of 1977, 1978 and 1979; MARTINDALE l 7 ; The pharmacological basis of therapeutics I I. Clinical models for the objective judgement of the effect of anti-rheumatics are still insufficient or lacking. Usually the effects on inflammatory reactions, often induced by means of a trauma, are tested on animal models. It would be convenient if the model could also be used to predict the anti-rheumatic effects. The aim of the present study was, using a standardized clinical model from known antiphlogistics, to select the drug that after surgical removal of the wisdom-tooth from the lower jaw effectively and safely prevents or reduces traumatic inflammatory reaction, without involving unjustified risks on application on a large scale. In this study, the prevention of postsurgical swelling, trismus and general feeling of illness is emphasized. A secondary aim was to establish a standardized clinical model to objectively test the antiphlogistic effects of antirheumatics.
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Material and methods The experiment was carried out on 126 healthy persons. After application of local anaesthesia, the mucoperiosteum was incised and reflected, If necessary, bone was removed by a saline cooled bur and the tooth was split in two. After removal of the molar, the mucoperiosteum was sutured in place by means of catgut.
The anti-inflammatory drugs tested were: (A) aspirin-like drugs ibuprofen - Brufen@ indomethacin - Indocid® naproxen - Naprosyne'P niflumic acid - Inflaryl® oxyphenylbutazone - Tanderilf' (B) a corticosteroid betamethasone - Celestones', and (C) an anti-fibrinolytic tranexamic acid Cyclokapron'P, which is used to prevent secondary hemorrhage and which may have antiphlogistic properties. A placebo served as a control. Glafenine (Glifanan'[') was provided as a pain-killer in case the antiphlogistic or placebo had no or insufficient analgesic effect. Selection ofpatients Patients visiting the out-patient department of an Oral Surgery Department to have a wisdom tooth removed from the lower jaw for which an incision followed by elevation of the mucoperiosteum was thought necessary, were asked to cooperate in the experiment. The eligible persons were further selected on the basis of the following criteria: - a blank anamnesis regarding general health; - presence of the second molar next to the wisdom tooth; - sufficient occlusal contacts for holding a bitefork, needed for a standardized photograph; - no beard; - unrestricted opening of the mouth; - no inflammatory symptoms; - no use of drugs; - no pregnancy or breast-feeding; - no tuberculosis in the anamnesis; - sound mental health. Patients conforming to these criteria were provisionally admitted to the research project. However, exclusion on account of the result of an examination by a specialist in internal medicine and the data obtained in the further course of taking an anamnesis, physical diagnostics and an investigation of blood and urine were still possible. Slight deviations in blood values were not reasons for excluding patients if in the entire examination no indications for an
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ZWAN, BOERING, WESSELlNG, SMIT SlBINGA AND VAN DER WEELE
underlying disease were found. In this way,71 females and 55 males were selected for participation in the experiment. The average age was 22 years and 8 months (max, 31 years, min, 17 years). Standardized questionnaire All data were noted on a standard questionnaire suitable for computer analysis> . This list with a total of 163 items provided information about: - sex, age, maximal opening of the mouth and oral temperature; - the number of postoperative days that were partially or entirely spent in bed, inability to work normally and swallowing difficulties; - post-surgical complications like secondary hemorrhage, alveolitis and. inflammation; - dietary information before and after the operation (breakfast on the morning of the operation or not and impeded normal food intake postoperatively); - side effects (documented by 20 relevant questions). Included ill the protocol were also : the number of lidocainfadrenalin carpules injected; the method of removing the impacted third molar subdivided into 3 catego ries : (3) after incision and elevation the mucoperiost; (b) after removal of bone by means of 3 salinecooled bur; (c) after separation of crown and roots; the duration of the operation from incision to suturing in 5 min units . Patients were examined on Monday at 9.00 a.m., oil Wednesday at 12.00a.m . and on Friday, the fourth day after the operation, at 9.00 a.m. A last check took place on Thursday, 24 days after the operation. On Monday the patient was subjected to the physical examination by the specialist in internal medicine. Blood and urine tests were performed. On Monday and on Wednesday the maximal opening ofthe mouth and the oral temperature were measured. A full face photograph was taken the same day. On Friday, the Wednesday examination was repeated, after which the questionnaire was completed and the blood and urine tests of Monday repeated . Measuring swelling , pain and trismus The reproducible method of VAN Gooi, et al," for measuring the swelling was chosen for its simplicity. Here by means of a bitefork covered with wax, the head is fixed in a permanent position in front of a camera. On the standardized photograph, which is printed en-face life-size, the left and right cheeks are traced on orthodontic tracing paper. The difference in facial contour at the level of one cheek on Wednesday and
Friday was compared to the pre-surgical photograph of Monday; this was measured by one and the same person with a magnifying glass, in units of 0.01 mm. The distance between the contour lines served as a measure of the swelling of the cheek. In addition to the drug to he tested or the placebo that had to be taken according to a fixed schedule, 18 tablets of glafenine (200 mg each) were provided. The number of glafenine tablets that was taken postoperatively served as a measure of pain . A standard dosage of glafenine is said to have no anti-inflammatory properties in humans. The maximal opening of the mouth pre- and postoperatively was measured between the upper and lower incisors by means of a marking gauge. To achieve a good result it is important to practise this with the patient once in advance. WOOD et a/.'3 have shown that this provides more reliable results. Presupposing that the maximal opening of the mouth is impeded before pain develops, the measure was taken under slight pressure. Trismus was defined according to the following formula : . presurg. - postsurg. opening of the mouth tnsmus = 0-_--=----''--_--='-:-::.--=-,=-__.,..-__ presurg, opening of the mouth x 100%. Selection of drugs Antiphlogistics can be divided into corticosteroids and so-called "non-steroid anti-inflammatory drugs" (NSAID's). The elaborate side effects of both categories especially during long-term use are wellknown. Little was known, at the beginning of this research-project in 1975,concerning the effectiveness and side effects of drug therapy used after removal of the lower third molar. For this study, betamethasone (corticosteroid), ibuprofen, indomethacin, naproxen, niflumic acid, oxyphenylbutazone (NSAID's), and tranexarnic acid were chosen . The latter drug is an anti-fibrinolytic agent with antiphlogistic properties. An intake schedule was chosen of 4 times per 24 h to obtain equal intervals. The drug was taken immediately before the operation. This dose was then doubled, corresponding to the joint morning and afternoon doses. Below, a survey is given of the dosages used in this study (Table I).
Results The influence of the drugs on post-operative pain, swelling and trismus as well as on complaints about swallowing, possible aspiration and a general feeling of illness, manifested
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ORAL SURGERY AND ANTIPHLOGISTICS Table I. Survey of dosages of antiphlogistic drugs Drug
Dosage/day
Ibuprofen Indomethacin Naproxen Nuflumic acid Oxyphenylbutazone Betamethasone
1200 mg 150 mg 750 mg 1000 mg 600 mg 14.5 mg total, decreasing
Tranexamic acid
2000 mg
over 4 days
by fever and inability to work will now be discussed. In design the study comprised a double blind experiment set up in parallel with a placebo and a control. Data were tested two-sided, 000parametrically. A 5% significance level was chosen. Some characteristics concerning patients and the operational technique were correlated with the degree of swelling, trismus and pain. Whether every characteristic was equally distributed among the different drug groups was also investigated. If this was not the case, a significant difference might have been caused by one of the characteristics, and not by the drug being taken. The effects ofdrugs on pain, swelling and trismus
For an easy survey and comparison, the values found have been put together in Table 2. In the
first column under M, the mean number of glafenine tablets taken during the total postsurgical period, is recorded. The second column contains the means of swelling in units of 0.1 mm on the second day after the operation. In the third column the trismus is presented. N represents the number of patients. The average refers to M; p.s. stands forpost-surgically. The placebo group and the drug groups differ significantly in the number of glafenine tablets taken (Mann-Whitney U-test), except for the difference with the oxyphenylbutazone and tranexamic acid groups. The Mann-Whitney Utest showed that only betamethasone differs from the placebo group as far as the scores for swelling and trismus on the second day after the operation were concerned. Betamethasone showed a significantly greater reduction of swelling than all the other drugs (MannWhitney U-test). Age, body surface, sex, menstrual cycle or use of the pill, feeding habits, the number of tablets of glafenine taken, the number of carpules of local anaesthesia and the position of the wisdom tooth did not appear to be correlated with the degree of swelling, trismus or pain. The duration of the operation was equally divided over the groups. This is important because of the positive correlation between operation time and postoperative discomfort, such as swelling, trismus and pain.
Table 2. Survey of the degree of pain, swelling and trismus Glafenine tablets 4th day p.s.
Ibuprofen Indomethacin Naproxen Niflumic acid Oxyphenylbutazon Betamethasone Tranexamic acid Placebo
Swelling (0.1 mm) 2nd day p.s.
Trismus (%) 2nd day p.s.
M
N
M
N
M
N
1.6 1.7 1.5 0.8 2.6 0.9 4.2 4,9
15 16 14 18 12 16 17 16
35 36 36 34 35 15 30 42
13
34 33 33 34 30 25 35 41
16 16 18 12 16 16 15
15
15 14 10 13
14 15
15
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The influence of drugs on post-surgical swallowing, complaints and general feeling of malaise Swallowing difficulties occurred in 41% of all patients. Excluding the day of the operation, swallowing is still a problem in one third of all patients. Over an average period of 1.75 days, swallowing difficulties appeared in the placebo group. Patients of the other groups had significantly less complaints. Using the Mann-Whitney Ll-test, it could be demonstrated that users of ibuprofen, niflumic acid and indomethacin had significantly fewer days of swallowing complaints than patients in the placebo group. The body temperature is expected to be increased in the period right after the operation. With the exception of tranexamic acid, the drugs examined are recommended for their anti-pyretic and anti-phlogistic properties. A standard dosage of glafenine is said to have no anti-inflammatory properties in humans. It would be important to know whether a rise of temperature could be reduced by some of the drugs. A calibrated mercury thermometer was placed under the tongue on the contralateral side from the operation area for 5 min. No significant difference could be demonstrated between test- and control groups. Per group, pre- and post-operative data of individual persons were compared using the Wilcoxon test for symmetry. No significant differences occurred here either. Bed rest post-operatively was unnecessary in 72 (57%) of the 126 patients. More than 25% (35 persons) stayed in bed for I day. It appeared that 12 persons stayed in bed for 2 days, 4 persons for 3 days and I for 5 days. A day partially spent in bed was counted as I whole day. For 124 of the patients, the number of days that they were able to do their work normally is known. A quarter of them (35) lost no days. Of the 89 remaining patients, 38could not work for I day, 20 for 2, 5 for 3 days and 8 were not able to work for 4 days. The fact that 18 patients reported 5 days work lost gives reason to
suspect that the second check-up was considered by them as a declaration of health, after which they had to go back to work. The results of unfitness for work are not associated with bed. The tranexamic acid group and the placebo group resulted in the highest scores. Probably the question about unfitness for work has been differently interpreted by many patients. Perhaps those who waited for the last check-up have disturbed the picture. Use ofdrugs and effect on the occurrence oflocal complications The most important post-surgical complications are secondary hemorrhage, postsurgical inflammation and drysocket. Secondary hemorrhage occurred only twice. A submucuous abscess developed in 5 patients. In 3 of them this abscess developed 3050 days after the operation; in all 3 cases sequesters had been formed. By alveolitis (dry socket) is meant an acute superficial inflammation of the bony alveolus walls which occurs 2-4 days after removal of a tooth and is attended with pain and a foetid content of the alveolus, Out of 126 patients in our study, alveolitis occurred in 21 cases. A percentage of 2-4% of alveolitis is generally mentioned in literature. In some Scandinavian publications, much higher percentages can be found, e.g. GERSEL-PEDERSEN 10 gives 10%. A good survey concerning this subject is reported by BIRN 5 and GERsEL-PEDERSEN ' C • The spread of the occurrence of alveolitis over the different drug groups was equal. A striking fact was the occurrence of alveolitis in 19 out of 71 females and in only 2 out of 55 males. This difference is highly significant (x'). It is known that women show an increased fibrinolysis during menstruation. This may explain a 50% higher probability of this complication in females as compared to males. GERSEL-PEDERSEN'o found not one patient with alveolitis during menstruation, but in 31.3% of women taking the pill. This led to his surprising advice to treat female patients when they were having their period.
ORAL SURGERY AND ANTIPHLOGISTICS
From the answers to the question as to when the first day of the last menstruation had occurred, it appeared that 8 women were in the first seven days of the cycle. Out of these, 2 women developed alveolitis. Since in total, 19 out of7l women developed alveoli tis, this does not present a significant difference. There is no difference in the occurrence of alveolitis when comparing the number of women with alveolitis who were in the first 14 days of the menstrual cycle, with the occurrence frequency in other women. The history of the use of oral contraceptives was known for 59 out of 71 women. Alveolitis occurred 2.4 times as frequently in women taking the pill as in those not (12 over 5). Side effects From the treatment of patients suffering from rheumatoid arthritis, it is known that long-term use of antiphlogistics may have serious side effects. Drugs showing these side effects also in short term use are not suitable for large-scale application in oral surgery. Therefore it is of the utmost importance to test the administered drugs. This was achieved by means of a questionnaire and a general medical examination. Side effects according to questionnaire From the answers to the questionnaire it appeared that many patients had more than one complaint. In such a way, a total number of229 times a side effect was scored. The number of patients of the total group, 126 alltogether, reduced by 33 patients at most without any side effects, gives 93 patients with an average of 2.5 complaints. Urticaria did not occur in any of the 126 patients examined. The complaints of 15 patients could not be classed under any of the 22 items. The remaining 214 complaints are often sleepiness and drowsiness, followed by headache and excess salivation. This is in agreement with data on placebo reactions in the literature'. That these complaints are often not related to
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the drugs used is shown by their equal distribution over the groups and by the fact that all patients continued taking the drug, the complaints disappearing or diminishing during the week. The dosage was constant for all the patients in one group. One may therefore assume that the number of days patients complained of sleepiness and drowsiness is directly related to a possible side effect of the drug. However, statistically it can be shown that in comparison with the placebo group there are no significant differences. After grouping together, the difference between placebo and indomethacin is significantly disadvantageous to the latter drug (x'). Indomethacin was associated with significantly more headache, dizziness and singing in the ears than the placebo treatment. Persons having breakfast before the administration of the drug, might have had a smaller chance of side effects. To test this, all persons who had more than one side effect were compared with the patients without complaints. 2 patients only who had not breakfasted remained without complaints. Clearly, those patients who had a empty stomach on the morning of the operation showed a significantly increased chance of one or more side effects (x'). A relation to side effects in the area of the gastro-intestinal tract itself could not be found. Serious side effects did not occur. Most "side effects" are probably reactions due to the operation event especially with its stress, than real effects caused by the administered drugs. Side effects according to general medical examination To the general physical examination a blood and urine test were added. It was important to determine whether dosages of short duration could also bring about significant pathological changes. ESR, Hb, Hcrt, trombocytes, leucocytes, alkaline phosphatase, GOT, GPT, LDR and creatinine were tested. The bleeding time, trombocyte aggregation and disaggregation were judged simultaneously. In this way insight
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was obtained into changes in blood morphology, chemistry and blood coagulation, and into the influence on the liver and kidney functions. Urine was checked for glucose, protein and sediment. Differences among the differen t groups of the study before the operation, are so small that they can be counted as one population (Kruskal-Wallis). Because allergic reactions, which belong to the much feared side effects of some of the drugs examined, did not occur, large deviations in the examination values of blood and urine were not found. The significant differences between the drug groups and the placebo group can be regarded as a dosedependent result. Significant differences in comparison with the placebo group were found with betamethasone (leucocytosis) and with indomethacin (diminished hematocrit); additional differences were found with indomethacin as well as with niflumic acid and naproxen (prolonged bleeding time), naproxen (diminished trombocyte aggregation) and indomethacin (increased disaggregation). In the chemical analysis of blood and in the analysis ofurine, no significant differences were found after the operation. With Wilcoxon's test for symmetry, however, many significant differences could be shown in the results of the blood and urine analysis before and after the operation, as compared to normal. This means that both the operation and intake of drugs can be responsible for these shifts.
Discussion After comparing the effects of the drugs tested, the effect of betamethasone stands out clearly. The pain after the operation is reduced by approximately 80%, swelling by 65% and trismus by 40%. HOOLEY et al'! have carried out a comparable study with betarnethasone, These authors found a reduction of pain by 50%, of swelling by 80% and of trismus by 55%. These authors let the patients take the betamethasone the night prior
to the operation. In other publications about betamethasone, the data found were confirmed without, however, the possibility ofa numerical comparison. Ibuprofen was only expected to have an effect on pain after the operation". In our material this same effect is seen, not only in the values found, but in the total number of glafenine tablets that were taken. In the literature the degree of effect of indomethacin isjudged varyingly. It is generally assumed that it achieves adequate pain reduction. In our study this effect, however, appeared to be only moderate. With subjective methods' the reduction of post-surgical swelling was judged to be slight. Measured with objective methods'S, the effect would not exceed the results in the placebo group. The slight, nonsignificant reduction of swelling in this study confirms results found in the literature. The trismus might be significantly reduced with indomethacin's. Although indomethacin, just like other antiphlogistic analgesics reduces trismus from 41% to about 33%, the difference is not significant in this study. Possibly the groups were too small to show this effect. In the literature only the good analgesic effect of naproxen is mentionedw-". This property is confirmed by this study. As far as the effect on trismus and swelling is concerned there is no difference with the other NSAID's. Niflumic acid gave the highest score of the antiphlogistic analgesics regarding the relief of pain. On an average only 0.8 tablets of glafenine were taken compared with 4.9 tablets in the placebo group. This analgesic effect is significantly higher when compared to the placebo group (;(2). The effect on swelling and trismus did not differ from the other anti-rheumatics, nor did it significantly differ from the results in the placebo group. The data in the literature, based on subjective tests, confirm these results. However, an objective test of equal value has never been published. Oxyphenylbutazone has very often been the subject of research. In many experiments, the
ORAL SURGERY AND ANTIPHLOGISTICS
standards are not sufficiently comparable and in most cases a statistical evaluation has been omitted. All papers report a reduction of pain. A reduction of postoperative swelling or trismus is also reported. VARLEY]] confirms this in a double blind experiment in which the swelling was measured with a pair of bow compasses and the degree of pain presented in three gradations. VAN GEEL 9 again confirms the significant reduction of pain by oxyphenylbutazone in a comparable experiment, as does HALSTRICK I4 • The latter even finds a reduction of the swelling by 40%, photographically measured. He starts his medication 3 days in advance. BVSTEDT' finds a significantly improved opening of the mouth and reduction of pain. The experiment of ALBUM et al,' proves that pain is counteracted well, but that there is no control on the intake of other analgesics. The trismus is reduced a little and there is also a reduction of the swelling by 15%. Statistical tests were not carried out in this study. In our experiment, the group of patients taking oxyphenylbutazone is rather small (12). However, the mean values and the tests seem to indicate a moderate effect, not significantly different from the placebo group. Tranexarnic acid, which in animal models was found to have a slight inhibitory effect on inflammation seems to give a reduction of postsurgical swelling. Because the difference with the placebo group is not significant, no further conclusion can be drawn from this. It is remarkable, that there is no effect on pain. In this study, the high percentage (17%) of dry socket is striking. An explanation for this could be that every patient with whom the pain did not ease after the first two days, but stayed the same or grew even worse and who had a foetid alveolus, was also considered to have alveolitis. Moreover, every patient had to come for a check-up. Large differences in the frequencies found of the occurrence of alveolitis may arise if only those patients are counted who report the recurrence of serious pain spontaneously, and who came back on their own
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initiative. In many papers these circumstances are not clearly described. The drug taken does not seem to influence the number of patients with alveoli tis. Neither does tranexamic acid, which seems to confirm the work of RITZAU I 9 • Local application of this drug is not sufficient to prevent alveolitis either!". The findings concerning the occurrence of alveolitis are generally in accordance with those found in the literature. If the occurrence of alveolitis depends on the oestragen level, the frequency of alveoli tis will drop during menstruation (the days no pill is taken). Another possibility is that the mini-pill, which contains less than 50 JIg of ethinyloestradiol, has no influence at all. As a whole, one could state that in this investigation, it has been proved that betamethasone largely prevents the development of pain, swelling and trismus after surgical removal of a third molar. All anti-rheumatics, except oxyphenylbutazone, have been shown to give a reduction of pain. In this respect niflumic acid has the strongest effect. The degree of swelling is reduced by these drugs by only 1520% and trismus by 25%. It is striking that tranexamic acid gives only a reduction of swelling. Compared with the anti-rheumatics, a different target in the inflammatory reaction could playa part in this. It was found impossible to establish the antipyretic qualities of the drugs recommended for these with the procedure followed. The spread of temperature is relatively large, which can be explained from the out-patient set-up. In view of the measured maxima, the rise of temperature as a consequence of the surgical removal of a third molar, will rarely be more than 1°C. In the only comparable experiment', no significant difference could be demonstrated either between the group of patients treated with oxyphenylbutazone and the placebo group. Almost 1- of all patients experienced difficulties with swallowing on the days following
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the operation. Based on the number of days of swallowing complaints, ibuprofen and niflumic acid showed a significant reduction in the number of swallowing difficulties. Betamethasone, which reduces pain and swelling most, does not stand out in this respect. Therefore, the assumption that swelling and pain are the most important causes oftbe swallowing complaints is not confirmed. A satisfactory explanation for this phenomenon was not found. Almost half of the patients felt so ill postoperatively that they went to bed. In this respect only tranexamic acid did not work better than placebo. The other drugs tested caused a significant reduction in the number of days of bed rest. Another way of finding out how well people felt was the question about the number of days they had not been able to work normally. Only ibuprofen significantly reduced the number of days people did not work. However, ibuprofen does not score very high in the reduction of pain and swelling. The ideas of work and the ability to work differed greatly from individual to individual when considering the distribution of days lost from work. Probably the question about the number of days people had to stay in bed gives more accurate information about the well-being of the patients.
Conclusion and practical implications With this study, insight was obtained into the short-term effects of a number of antiphlogistic drugs. To repress post-surgical inflammatory reactions after intra oral operations, drugs like ibuprofen, indomethacin, naproxen, niflumic acid and oxyphenylbutazone are not indicated. In this study they offered to be especially effective analgesics. The antiphlogistic capacities seem small. These drugs are aspirin-like drugs with serious side effects like:
- irritation of the digestive tract - extension of coagulation - allergic reactions, such as agranulocytosis which is seen most often after administration of oxyphenylbutazone. Tranexamic acid could have a slight antiphlogistic effect, which is a poorly described property. For further research of inflammatory reactions this may be of importance. The application ofcorticosteroids in a dosage over a period of 4 days is strongly recommended by this study and by the literature. The bad reputation these chemicals have is due to side effects that arise after long-term administration for chronic diseases. Serious side effects like allergic reactions are lacking. Illnesses like epilepsy, glaucoma, hypoparathyroidism and diabetes mellitus can become manifest; the latter two do not occur with short-term use. Absolute contra-indications are formed by an acute virus infection, e.g. herpes or a history of tuberculosis. Relative contra-indications are: stomach ulcer, psychiatric past, serious hypertension, diabetes mellitus, bacterial infections, tendency for thrombosis', young age, pregnancy. In the Department of Oral and Maxillofacial Surgery of the University Hospital in Groningen, we give corticosteroid treatment to all patients who will undergo a surgical removal of the lower third molar. A prescription for an ordinary analgesic will only be given to persons in whom a contra-indication for steroids exists. Because of the costs, there is a preference for prednisolon 32 tablets (5 mg each). Since the drug is to be administered preventively, the patient takes 8 tablets (5 mg each) in the operation room, preceding the removal of the wisdom tooth. The other 24 will be taken at home with written instructions. The intake schedule is as follows: day of operation first day after operation second day after operation third day after operation
4--4--3-3 2-2-2-2 2-2-1-1 1-1-1-1
ORAL SURGERY AND ANTIPHLOGISTICS
Patients undergoing a big elective operation, e.g. osteotomy, are administered betamethasone, according to the following schedule: 8 and 4 mg, in the drip at the beginning and the end of the operation, respectively. 4 and 2 mg, i.m, or orally, in the morning and on the evening of the following day, respectively. - 2 and I mg, respectively as immediately above. I mg in the morning. Antibiotics are given for a week. The clinical impression is positive, which is in agreement with the literature.
Recommendations for further research The aim of a further study could be: to obtain a better insight into the mechanism of the inflammatory reaction; to test the recently developed antiphlogistics (analgesics included) which selectively interfere in the course of the inflammatory mechanism; to improve the measurement of the swelling; to look for an objective measure for the diagnosis of alveolitis; to look for a relation between hormonal status and alveolitis. The comparative study of V AN GOOL 12 already provided a number of questions which, related to the existence of mediators and acute phase proteins, might give insight into the inflammatory reaction: what is the relation between pain, swelling and trismus? why do some patients have swelling, but no pain? why have others pain, but no swelling? why do all patients have trismus? Newly processed drugs must have different targets in the inflammatory reaction than corticosteroids and the now known antiphlogistics. The present anti-rheumatics do not
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differ much in targets and in effects and side effects, although new products are put on the market continually. The mutual relation between mediators, acute phase proteins, stages of the inflammatory reaction and the clinical inflammatory phenomena must be revealed. Also, the influence of drugs and if possible of anti-mediators, not only on mediators, but also on the clinical appearance of the inflammation, should be investigated. It seems possible to improve strongly on measurement of the swelling. Only BREYTENBACH 6 has compared several measuring methods. It is possible to compare the methods used in this experiment with the Scandinavian method in which a bitefork with pins attached to it is used to measure the swelling of the cheek. Application of rasters, of photogrammetric or holographic techniques also deserve attention. If the shape of the face could be determined with the help of a computer, so that after the operation the swelling could be calculated in volume units after subtraction, this would mean a great step forward. Perhaps echography and radar would also be an asset. To establish the relation between the development and the frequency of alveolitis and causative or therapeutic factors, an objective measure for the diagnosis of alveolitis must be found. Measuring the pH of the alveolus or the concentration of a chemical causing the foetide factor may be a possibility. It seems that the model of the patient undergoing a standardized operation like the third molar operative extraction isideally suited for further research.
References 1.
2.
ALBUM, B., et a!.: Bilateral surgical removal of impacted mandibular thirdmolar as a model for drug evaluation: a test with oxyphenbutazone
(Tanderil'['), Int. J. Oral Surg, 1977: 6: 177-189. ANDERSSON, L.: Combined prophylaxis of
haemorrhage and trombosis after prostatectomy. Acta Chir. Scand. 1965: 130: 393-398.
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3. BAZERQUE, P. M., et a!.: Use of indomethacin as an anti-inflammatory agent in patients subjected to exodontia. Rev. Asoc. Odontol. Argent. 1967: 55: 526-528. 4. BEECHER, H. K.: The powerful placebo. J. Am. Med. Assoc. 1955: 159: 1602-1607. 5. BIRN, H.: Etiology and pathogenesis of fibrinolytic alveolitis ("dry socket"). Int. J. Oral Surg, 1973: 2: 211-263. 6. BREYTENBACH, H. S.: Objective measurement of post-operative swelling. Int. J. Oral Surg, 1978: 7: 386-392. 7. BYSTEDT, H.: Clinical and haemotological investigation of Rheumapax'P in surgical removal ofimpacted wisdom teeth from the mandible. Int. J. Oral Surg. 1976: 5: -6-70. 8. DUKES, M. N. G. : Meyler's side effects ofdrugs. A survey of unwanted effects of drugs reported in 1972-1975 (VIII). Excerpta Medica, Amsterdam 1975. 9. GEEL, C.J. E. VAN: Erfahrungen mit Tanderil® in Schweiz. Monatschr. der Kieferchirurgie. Zahnheilkd. 1968: 78: 257-259. 10. GERSEL-PEDERSEN, N.: Tranexamlc acid in alveolar sockets in the prevention of alveolitis sicca dolorosa, Int. J. Oral Surg. 1979: 8: 421-429. 11. GOODMAN, L. S. & A. GILMAN: The pharmacological basis of therapeutics, 6th edition. Mac Millan, New York 1980. 12. GOOL, A. V. VAN: De verstandkies in de onderkaak. Groningen, thesis, 1975. 13. GOOL, A. V. VAN, et a!.: A photographic method of assessing swelling following third molar removal. Int. J. Oral Surg, 1975: 4: 121-129. 14. HALSTRICK, F.: Entwicklung eines photographischen Messverfahrens postoperative Odeme nach Entfernung unterer Weisheitsziihne. (In Verbindung mit einem Doppelblindversuch tiber Tanderile ), Kiel, thesis, 1974. 15. HOOLEY, J. R., et a!. : Betamethasone in traumatic oral surgery. J. Oral Surg, 1969: 27: 398-403.
16. LOKKEN, P., et al.: Bilateral surgical removal of impacted lower third molar teeth as a model for drug evaluation: a test with ibuprofen. Eur. J. Clin. Pharmacol. 1975: 8: 209-216. 17. Martindale, the extra pharmacopoeia. Incorporating Squire's Companion. 27th edition. AINLY WADE et a!. (eds.) London, Pharmaceutical Pr., 1977. 18. PETERSEN, J. K.: Anti-inflammatory and analgetic effects of indomethacin following removal of impacted mandibular third molars. Int. J. Oral Surg. 1975: 4: 267-276. 19. RITZAu, M.: The prophylactic use of tranexamic acid (cyclokapron) on alveolitis sicca dolorosa, Int. J. Oral Surg. 1973; 2: 196--199. 20. RUEDY, J.: A comparison of the analgesic efficacy of naproxen and acetylsalicylic acid-codeine in patients with pain after dental surgery. Scand. J. Rheumatol. 1973: suppl. 2: 60-63. 21. STETSON, J. B., et al.: Analgesic activity of oral naproxen in patients with postoperative pain. Scand. J. Rheumatol. 1973: supp!. 2: 50-55. 22. VARLEY, E.: Control of swelling, trismus and pain after the removal of impacted wisdom-teeth. In: Die posttraumatische Entziindung. Hrsg. von J. Lindner et al. Bern etc., Huber 1976, 237-244. 23. WOOD, G. D., et a!.: A comparison of three methods of measuring maximal opening of the mouth. J. Oral Surg. 1979: 37: 175-177. 24. ZWAN, J. VAN DER: Verstandskies en antiphlogistica. Groningen, thesis 1980.
Address:
J. van der Zwan Department of Oral Surgery University Hospital
Oostersingel Sv 9711 XE Groningen The Netherlands
Review article
(Keywords: molar, lower third; removal a/molar; antiphlcgistics : trismus: pain)
The lower third molar and antiphlogistics Effects of betamethasone, ibuprofen, indomethacin, naproxen, niflumic acid, oxyphenylbutazone, tranexamic acid and glafenine on the patient's condition after surgical removal of a lower third molar J. VAN DER ZWAN, G. BOERING, H. WESSELING, C. TH. SMIT SIBINGA AND L. TH. VAN DER WEELE
DepartmentsofOral Surgery, and Internal Medicine, University Hospital ..Department ofClinical Pharmacology, Mathematical Center, State University, Groningen, The Netherlands
ABSTRACT - A multidisciplinary, double blind, parallel placebo controlled investigation was made to find an effective anti-inflammatory drug which prevents postoperative swelling, trismus and a general feeling of malaise. An additional aim was to evaluate objectively the anti-inflammatory properties of anti-rheumatics. In 126 healthy patients, who were without complaints, the lower third molar was surgically removed. A drug had to be taken orally according to a fixed scheme for 4 days. Glafenine had to be taken in case of pain. The number of tablets taken was used to quantify pain. Swelling of the cheek was measured photographically and trismus was deducible from the maximal mouth-opening. The drugs investigated were betamethasone 14.5 mg decreasing over 4 days, ibuprofen 1200 mg/day, indomethacin 150 mg/day, naproxen 750 mg/day, niflumic acid 1000mg/day, oxyphenylbutazone 600 mg/day and tranexamic acid 2000 mg/day. Oxyphenylbutazone and tranexamic acid were not significantly different from placebo in their pain-killing effects. Betamethasone prevents swelling and trismus significantly more than the placebo. Betamethasone is significantly better than the other drugs in the prevention of swelling. Reduction of the swelling by anti-rheumatics may be 10-15% and a 20% reduction of trismus is to be expected. The strongest analgesic is niflumic acid. Tranexamic acid may perhaps reduce the swelling by 28%. The questionnaire and the blood- and urine-test Showed that anti-rheumatics have to be considered to be acetylsalicylic acid-like drugs. Serious side effects have been reported previously for anti-rheumatics. When taken for a short time, corticosteroids are very safe drugs with a few mild side-effects. Many patients experience a slight euphoria. Betamethasone, in a dosage of 14.5 mg decreasingly divided over 4 days prevents pain by 80%, swelling by 65% and trismus by 40% compared with the placebo group. This safe drug is recommended in elective surgery.
0300-0785/82/060340-11$02.50/0 © 1982 Munksgaard, Copenhagen
ORAL SURGERY AND ANTIPHLOGISTICS
Counteracting post-operative complaints after surgical removal of the wisdom-tooth from the lower jaw has already been the subject of research many times. VAN GOOL I 2 was able to establish that pain, swelling and trismus were reduced by: making a vertical relaxing incision; little use offorce for the removal of the tooth; no plug in the alveolus; no primary closing of the wound; short duration of the operation. The development of post-surgical swelling and trismus and malaise remains a problem in spite of application of the principles mentioned. A good and safe antiphlogistic drug is clearly still needed. A complete literature survey of their applications in oral surgery is to be found as part of a thesis". The literature concerning side effects can be found completely brought up to date in several reference books, e.g, Meyler's side effects of drugs", with its annual supplements of 1977, 1978 and 1979; MARTINDALE l 7 ; The pharmacological basis of therapeutics I I. Clinical models for the objective judgement of the effect of anti-rheumatics are still insufficient or lacking. Usually the effects on inflammatory reactions, often induced by means of a trauma, are tested on animal models. It would be convenient if the model could also be used to predict the anti-rheumatic effects. The aim of the present study was, using a standardized clinical model from known antiphlogistics, to select the drug that after surgical removal of the wisdom-tooth from the lower jaw effectively and safely prevents or reduces traumatic inflammatory reaction, without involving unjustified risks on application on a large scale. In this study, the prevention of postsurgical swelling, trismus and general feeling of illness is emphasized. A secondary aim was to establish a standardized clinical model to objectively test the antiphlogistic effects of antirheumatics.
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Material and methods The experiment was carried out on 126 healthy persons. After application of local anaesthesia, the mucoperiosteum was incised and reflected, If necessary, bone was removed by a saline cooled bur and the tooth was split in two. After removal of the molar, the mucoperiosteum was sutured in place by means of catgut.
The anti-inflammatory drugs tested were: (A) aspirin-like drugs ibuprofen - Brufen@ indomethacin - Indocid® naproxen - Naprosyne'P niflumic acid - Inflaryl® oxyphenylbutazone - Tanderilf' (B) a corticosteroid betamethasone - Celestones', and (C) an anti-fibrinolytic tranexamic acid Cyclokapron'P, which is used to prevent secondary hemorrhage and which may have antiphlogistic properties. A placebo served as a control. Glafenine (Glifanan'[') was provided as a pain-killer in case the antiphlogistic or placebo had no or insufficient analgesic effect. Selection ofpatients Patients visiting the out-patient department of an Oral Surgery Department to have a wisdom tooth removed from the lower jaw for which an incision followed by elevation of the mucoperiosteum was thought necessary, were asked to cooperate in the experiment. The eligible persons were further selected on the basis of the following criteria: - a blank anamnesis regarding general health; - presence of the second molar next to the wisdom tooth; - sufficient occlusal contacts for holding a bitefork, needed for a standardized photograph; - no beard; - unrestricted opening of the mouth; - no inflammatory symptoms; - no use of drugs; - no pregnancy or breast-feeding; - no tuberculosis in the anamnesis; - sound mental health. Patients conforming to these criteria were provisionally admitted to the research project. However, exclusion on account of the result of an examination by a specialist in internal medicine and the data obtained in the further course of taking an anamnesis, physical diagnostics and an investigation of blood and urine were still possible. Slight deviations in blood values were not reasons for excluding patients if in the entire examination no indications for an
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ZWAN, BOERING, WESSELlNG, SMIT SlBINGA AND VAN DER WEELE
underlying disease were found. In this way,71 females and 55 males were selected for participation in the experiment. The average age was 22 years and 8 months (max, 31 years, min, 17 years). Standardized questionnaire All data were noted on a standard questionnaire suitable for computer analysis> . This list with a total of 163 items provided information about: - sex, age, maximal opening of the mouth and oral temperature; - the number of postoperative days that were partially or entirely spent in bed, inability to work normally and swallowing difficulties; - post-surgical complications like secondary hemorrhage, alveolitis and. inflammation; - dietary information before and after the operation (breakfast on the morning of the operation or not and impeded normal food intake postoperatively); - side effects (documented by 20 relevant questions). Included ill the protocol were also : the number of lidocainfadrenalin carpules injected; the method of removing the impacted third molar subdivided into 3 catego ries : (3) after incision and elevation the mucoperiost; (b) after removal of bone by means of 3 salinecooled bur; (c) after separation of crown and roots; the duration of the operation from incision to suturing in 5 min units . Patients were examined on Monday at 9.00 a.m., oil Wednesday at 12.00a.m . and on Friday, the fourth day after the operation, at 9.00 a.m. A last check took place on Thursday, 24 days after the operation. On Monday the patient was subjected to the physical examination by the specialist in internal medicine. Blood and urine tests were performed. On Monday and on Wednesday the maximal opening ofthe mouth and the oral temperature were measured. A full face photograph was taken the same day. On Friday, the Wednesday examination was repeated, after which the questionnaire was completed and the blood and urine tests of Monday repeated . Measuring swelling , pain and trismus The reproducible method of VAN Gooi, et al," for measuring the swelling was chosen for its simplicity. Here by means of a bitefork covered with wax, the head is fixed in a permanent position in front of a camera. On the standardized photograph, which is printed en-face life-size, the left and right cheeks are traced on orthodontic tracing paper. The difference in facial contour at the level of one cheek on Wednesday and
Friday was compared to the pre-surgical photograph of Monday; this was measured by one and the same person with a magnifying glass, in units of 0.01 mm. The distance between the contour lines served as a measure of the swelling of the cheek. In addition to the drug to he tested or the placebo that had to be taken according to a fixed schedule, 18 tablets of glafenine (200 mg each) were provided. The number of glafenine tablets that was taken postoperatively served as a measure of pain . A standard dosage of glafenine is said to have no anti-inflammatory properties in humans. The maximal opening of the mouth pre- and postoperatively was measured between the upper and lower incisors by means of a marking gauge. To achieve a good result it is important to practise this with the patient once in advance. WOOD et a/.'3 have shown that this provides more reliable results. Presupposing that the maximal opening of the mouth is impeded before pain develops, the measure was taken under slight pressure. Trismus was defined according to the following formula : . presurg. - postsurg. opening of the mouth tnsmus = 0-_--=----''--_--='-:-::.--=-,=-__.,..-__ presurg, opening of the mouth x 100%. Selection of drugs Antiphlogistics can be divided into corticosteroids and so-called "non-steroid anti-inflammatory drugs" (NSAID's). The elaborate side effects of both categories especially during long-term use are wellknown. Little was known, at the beginning of this research-project in 1975,concerning the effectiveness and side effects of drug therapy used after removal of the lower third molar. For this study, betamethasone (corticosteroid), ibuprofen, indomethacin, naproxen, niflumic acid, oxyphenylbutazone (NSAID's), and tranexarnic acid were chosen . The latter drug is an anti-fibrinolytic agent with antiphlogistic properties. An intake schedule was chosen of 4 times per 24 h to obtain equal intervals. The drug was taken immediately before the operation. This dose was then doubled, corresponding to the joint morning and afternoon doses. Below, a survey is given of the dosages used in this study (Table I).
Results The influence of the drugs on post-operative pain, swelling and trismus as well as on complaints about swallowing, possible aspiration and a general feeling of illness, manifested
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ORAL SURGERY AND ANTIPHLOGISTICS Table I. Survey of dosages of antiphlogistic drugs Drug
Dosage/day
Ibuprofen Indomethacin Naproxen Nuflumic acid Oxyphenylbutazone Betamethasone
1200 mg 150 mg 750 mg 1000 mg 600 mg 14.5 mg total, decreasing
Tranexamic acid
2000 mg
over 4 days
by fever and inability to work will now be discussed. In design the study comprised a double blind experiment set up in parallel with a placebo and a control. Data were tested two-sided, 000parametrically. A 5% significance level was chosen. Some characteristics concerning patients and the operational technique were correlated with the degree of swelling, trismus and pain. Whether every characteristic was equally distributed among the different drug groups was also investigated. If this was not the case, a significant difference might have been caused by one of the characteristics, and not by the drug being taken. The effects ofdrugs on pain, swelling and trismus
For an easy survey and comparison, the values found have been put together in Table 2. In the
first column under M, the mean number of glafenine tablets taken during the total postsurgical period, is recorded. The second column contains the means of swelling in units of 0.1 mm on the second day after the operation. In the third column the trismus is presented. N represents the number of patients. The average refers to M; p.s. stands forpost-surgically. The placebo group and the drug groups differ significantly in the number of glafenine tablets taken (Mann-Whitney U-test), except for the difference with the oxyphenylbutazone and tranexamic acid groups. The Mann-Whitney Utest showed that only betamethasone differs from the placebo group as far as the scores for swelling and trismus on the second day after the operation were concerned. Betamethasone showed a significantly greater reduction of swelling than all the other drugs (MannWhitney U-test). Age, body surface, sex, menstrual cycle or use of the pill, feeding habits, the number of tablets of glafenine taken, the number of carpules of local anaesthesia and the position of the wisdom tooth did not appear to be correlated with the degree of swelling, trismus or pain. The duration of the operation was equally divided over the groups. This is important because of the positive correlation between operation time and postoperative discomfort, such as swelling, trismus and pain.
Table 2. Survey of the degree of pain, swelling and trismus Glafenine tablets 4th day p.s.
Ibuprofen Indomethacin Naproxen Niflumic acid Oxyphenylbutazon Betamethasone Tranexamic acid Placebo
Swelling (0.1 mm) 2nd day p.s.
Trismus (%) 2nd day p.s.
M
N
M
N
M
N
1.6 1.7 1.5 0.8 2.6 0.9 4.2 4,9
15 16 14 18 12 16 17 16
35 36 36 34 35 15 30 42
13
34 33 33 34 30 25 35 41
16 16 18 12 16 16 15
15
15 14 10 13
14 15
15
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ZWAN, HOERING, WESSELING, SMIT SIBINGA AND VAN DER WEELE
The influence of drugs on post-surgical swallowing, complaints and general feeling of malaise Swallowing difficulties occurred in 41% of all patients. Excluding the day of the operation, swallowing is still a problem in one third of all patients. Over an average period of 1.75 days, swallowing difficulties appeared in the placebo group. Patients of the other groups had significantly less complaints. Using the Mann-Whitney Ll-test, it could be demonstrated that users of ibuprofen, niflumic acid and indomethacin had significantly fewer days of swallowing complaints than patients in the placebo group. The body temperature is expected to be increased in the period right after the operation. With the exception of tranexamic acid, the drugs examined are recommended for their anti-pyretic and anti-phlogistic properties. A standard dosage of glafenine is said to have no anti-inflammatory properties in humans. It would be important to know whether a rise of temperature could be reduced by some of the drugs. A calibrated mercury thermometer was placed under the tongue on the contralateral side from the operation area for 5 min. No significant difference could be demonstrated between test- and control groups. Per group, pre- and post-operative data of individual persons were compared using the Wilcoxon test for symmetry. No significant differences occurred here either. Bed rest post-operatively was unnecessary in 72 (57%) of the 126 patients. More than 25% (35 persons) stayed in bed for I day. It appeared that 12 persons stayed in bed for 2 days, 4 persons for 3 days and I for 5 days. A day partially spent in bed was counted as I whole day. For 124 of the patients, the number of days that they were able to do their work normally is known. A quarter of them (35) lost no days. Of the 89 remaining patients, 38could not work for I day, 20 for 2, 5 for 3 days and 8 were not able to work for 4 days. The fact that 18 patients reported 5 days work lost gives reason to
suspect that the second check-up was considered by them as a declaration of health, after which they had to go back to work. The results of unfitness for work are not associated with bed. The tranexamic acid group and the placebo group resulted in the highest scores. Probably the question about unfitness for work has been differently interpreted by many patients. Perhaps those who waited for the last check-up have disturbed the picture. Use ofdrugs and effect on the occurrence oflocal complications The most important post-surgical complications are secondary hemorrhage, postsurgical inflammation and drysocket. Secondary hemorrhage occurred only twice. A submucuous abscess developed in 5 patients. In 3 of them this abscess developed 3050 days after the operation; in all 3 cases sequesters had been formed. By alveolitis (dry socket) is meant an acute superficial inflammation of the bony alveolus walls which occurs 2-4 days after removal of a tooth and is attended with pain and a foetid content of the alveolus, Out of 126 patients in our study, alveolitis occurred in 21 cases. A percentage of 2-4% of alveolitis is generally mentioned in literature. In some Scandinavian publications, much higher percentages can be found, e.g. GERSEL-PEDERSEN 10 gives 10%. A good survey concerning this subject is reported by BIRN 5 and GERsEL-PEDERSEN ' C • The spread of the occurrence of alveolitis over the different drug groups was equal. A striking fact was the occurrence of alveolitis in 19 out of 71 females and in only 2 out of 55 males. This difference is highly significant (x'). It is known that women show an increased fibrinolysis during menstruation. This may explain a 50% higher probability of this complication in females as compared to males. GERSEL-PEDERSEN'o found not one patient with alveolitis during menstruation, but in 31.3% of women taking the pill. This led to his surprising advice to treat female patients when they were having their period.
ORAL SURGERY AND ANTIPHLOGISTICS
From the answers to the question as to when the first day of the last menstruation had occurred, it appeared that 8 women were in the first seven days of the cycle. Out of these, 2 women developed alveolitis. Since in total, 19 out of7l women developed alveoli tis, this does not present a significant difference. There is no difference in the occurrence of alveolitis when comparing the number of women with alveolitis who were in the first 14 days of the menstrual cycle, with the occurrence frequency in other women. The history of the use of oral contraceptives was known for 59 out of 71 women. Alveolitis occurred 2.4 times as frequently in women taking the pill as in those not (12 over 5). Side effects From the treatment of patients suffering from rheumatoid arthritis, it is known that long-term use of antiphlogistics may have serious side effects. Drugs showing these side effects also in short term use are not suitable for large-scale application in oral surgery. Therefore it is of the utmost importance to test the administered drugs. This was achieved by means of a questionnaire and a general medical examination. Side effects according to questionnaire From the answers to the questionnaire it appeared that many patients had more than one complaint. In such a way, a total number of229 times a side effect was scored. The number of patients of the total group, 126 alltogether, reduced by 33 patients at most without any side effects, gives 93 patients with an average of 2.5 complaints. Urticaria did not occur in any of the 126 patients examined. The complaints of 15 patients could not be classed under any of the 22 items. The remaining 214 complaints are often sleepiness and drowsiness, followed by headache and excess salivation. This is in agreement with data on placebo reactions in the literature'. That these complaints are often not related to
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the drugs used is shown by their equal distribution over the groups and by the fact that all patients continued taking the drug, the complaints disappearing or diminishing during the week. The dosage was constant for all the patients in one group. One may therefore assume that the number of days patients complained of sleepiness and drowsiness is directly related to a possible side effect of the drug. However, statistically it can be shown that in comparison with the placebo group there are no significant differences. After grouping together, the difference between placebo and indomethacin is significantly disadvantageous to the latter drug (x'). Indomethacin was associated with significantly more headache, dizziness and singing in the ears than the placebo treatment. Persons having breakfast before the administration of the drug, might have had a smaller chance of side effects. To test this, all persons who had more than one side effect were compared with the patients without complaints. 2 patients only who had not breakfasted remained without complaints. Clearly, those patients who had a empty stomach on the morning of the operation showed a significantly increased chance of one or more side effects (x'). A relation to side effects in the area of the gastro-intestinal tract itself could not be found. Serious side effects did not occur. Most "side effects" are probably reactions due to the operation event especially with its stress, than real effects caused by the administered drugs. Side effects according to general medical examination To the general physical examination a blood and urine test were added. It was important to determine whether dosages of short duration could also bring about significant pathological changes. ESR, Hb, Hcrt, trombocytes, leucocytes, alkaline phosphatase, GOT, GPT, LDR and creatinine were tested. The bleeding time, trombocyte aggregation and disaggregation were judged simultaneously. In this way insight
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ZWAN, BOERING, WESSELING, SMlT SIBINGA AND VAN DER WEELE
was obtained into changes in blood morphology, chemistry and blood coagulation, and into the influence on the liver and kidney functions. Urine was checked for glucose, protein and sediment. Differences among the differen t groups of the study before the operation, are so small that they can be counted as one population (Kruskal-Wallis). Because allergic reactions, which belong to the much feared side effects of some of the drugs examined, did not occur, large deviations in the examination values of blood and urine were not found. The significant differences between the drug groups and the placebo group can be regarded as a dosedependent result. Significant differences in comparison with the placebo group were found with betamethasone (leucocytosis) and with indomethacin (diminished hematocrit); additional differences were found with indomethacin as well as with niflumic acid and naproxen (prolonged bleeding time), naproxen (diminished trombocyte aggregation) and indomethacin (increased disaggregation). In the chemical analysis of blood and in the analysis ofurine, no significant differences were found after the operation. With Wilcoxon's test for symmetry, however, many significant differences could be shown in the results of the blood and urine analysis before and after the operation, as compared to normal. This means that both the operation and intake of drugs can be responsible for these shifts.
Discussion After comparing the effects of the drugs tested, the effect of betamethasone stands out clearly. The pain after the operation is reduced by approximately 80%, swelling by 65% and trismus by 40%. HOOLEY et al'! have carried out a comparable study with betarnethasone, These authors found a reduction of pain by 50%, of swelling by 80% and of trismus by 55%. These authors let the patients take the betamethasone the night prior
to the operation. In other publications about betamethasone, the data found were confirmed without, however, the possibility ofa numerical comparison. Ibuprofen was only expected to have an effect on pain after the operation". In our material this same effect is seen, not only in the values found, but in the total number of glafenine tablets that were taken. In the literature the degree of effect of indomethacin isjudged varyingly. It is generally assumed that it achieves adequate pain reduction. In our study this effect, however, appeared to be only moderate. With subjective methods' the reduction of post-surgical swelling was judged to be slight. Measured with objective methods'S, the effect would not exceed the results in the placebo group. The slight, nonsignificant reduction of swelling in this study confirms results found in the literature. The trismus might be significantly reduced with indomethacin's. Although indomethacin, just like other antiphlogistic analgesics reduces trismus from 41% to about 33%, the difference is not significant in this study. Possibly the groups were too small to show this effect. In the literature only the good analgesic effect of naproxen is mentionedw-". This property is confirmed by this study. As far as the effect on trismus and swelling is concerned there is no difference with the other NSAID's. Niflumic acid gave the highest score of the antiphlogistic analgesics regarding the relief of pain. On an average only 0.8 tablets of glafenine were taken compared with 4.9 tablets in the placebo group. This analgesic effect is significantly higher when compared to the placebo group (;(2). The effect on swelling and trismus did not differ from the other anti-rheumatics, nor did it significantly differ from the results in the placebo group. The data in the literature, based on subjective tests, confirm these results. However, an objective test of equal value has never been published. Oxyphenylbutazone has very often been the subject of research. In many experiments, the
ORAL SURGERY AND ANTIPHLOGISTICS
standards are not sufficiently comparable and in most cases a statistical evaluation has been omitted. All papers report a reduction of pain. A reduction of postoperative swelling or trismus is also reported. VARLEY]] confirms this in a double blind experiment in which the swelling was measured with a pair of bow compasses and the degree of pain presented in three gradations. VAN GEEL 9 again confirms the significant reduction of pain by oxyphenylbutazone in a comparable experiment, as does HALSTRICK I4 • The latter even finds a reduction of the swelling by 40%, photographically measured. He starts his medication 3 days in advance. BVSTEDT' finds a significantly improved opening of the mouth and reduction of pain. The experiment of ALBUM et al,' proves that pain is counteracted well, but that there is no control on the intake of other analgesics. The trismus is reduced a little and there is also a reduction of the swelling by 15%. Statistical tests were not carried out in this study. In our experiment, the group of patients taking oxyphenylbutazone is rather small (12). However, the mean values and the tests seem to indicate a moderate effect, not significantly different from the placebo group. Tranexarnic acid, which in animal models was found to have a slight inhibitory effect on inflammation seems to give a reduction of postsurgical swelling. Because the difference with the placebo group is not significant, no further conclusion can be drawn from this. It is remarkable, that there is no effect on pain. In this study, the high percentage (17%) of dry socket is striking. An explanation for this could be that every patient with whom the pain did not ease after the first two days, but stayed the same or grew even worse and who had a foetid alveolus, was also considered to have alveolitis. Moreover, every patient had to come for a check-up. Large differences in the frequencies found of the occurrence of alveolitis may arise if only those patients are counted who report the recurrence of serious pain spontaneously, and who came back on their own
347
initiative. In many papers these circumstances are not clearly described. The drug taken does not seem to influence the number of patients with alveoli tis. Neither does tranexamic acid, which seems to confirm the work of RITZAU I 9 • Local application of this drug is not sufficient to prevent alveolitis either!". The findings concerning the occurrence of alveolitis are generally in accordance with those found in the literature. If the occurrence of alveolitis depends on the oestragen level, the frequency of alveoli tis will drop during menstruation (the days no pill is taken). Another possibility is that the mini-pill, which contains less than 50 JIg of ethinyloestradiol, has no influence at all. As a whole, one could state that in this investigation, it has been proved that betamethasone largely prevents the development of pain, swelling and trismus after surgical removal of a third molar. All anti-rheumatics, except oxyphenylbutazone, have been shown to give a reduction of pain. In this respect niflumic acid has the strongest effect. The degree of swelling is reduced by these drugs by only 1520% and trismus by 25%. It is striking that tranexamic acid gives only a reduction of swelling. Compared with the anti-rheumatics, a different target in the inflammatory reaction could playa part in this. It was found impossible to establish the antipyretic qualities of the drugs recommended for these with the procedure followed. The spread of temperature is relatively large, which can be explained from the out-patient set-up. In view of the measured maxima, the rise of temperature as a consequence of the surgical removal of a third molar, will rarely be more than 1°C. In the only comparable experiment', no significant difference could be demonstrated either between the group of patients treated with oxyphenylbutazone and the placebo group. Almost 1- of all patients experienced difficulties with swallowing on the days following
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the operation. Based on the number of days of swallowing complaints, ibuprofen and niflumic acid showed a significant reduction in the number of swallowing difficulties. Betamethasone, which reduces pain and swelling most, does not stand out in this respect. Therefore, the assumption that swelling and pain are the most important causes oftbe swallowing complaints is not confirmed. A satisfactory explanation for this phenomenon was not found. Almost half of the patients felt so ill postoperatively that they went to bed. In this respect only tranexamic acid did not work better than placebo. The other drugs tested caused a significant reduction in the number of days of bed rest. Another way of finding out how well people felt was the question about the number of days they had not been able to work normally. Only ibuprofen significantly reduced the number of days people did not work. However, ibuprofen does not score very high in the reduction of pain and swelling. The ideas of work and the ability to work differed greatly from individual to individual when considering the distribution of days lost from work. Probably the question about the number of days people had to stay in bed gives more accurate information about the well-being of the patients.
Conclusion and practical implications With this study, insight was obtained into the short-term effects of a number of antiphlogistic drugs. To repress post-surgical inflammatory reactions after intra oral operations, drugs like ibuprofen, indomethacin, naproxen, niflumic acid and oxyphenylbutazone are not indicated. In this study they offered to be especially effective analgesics. The antiphlogistic capacities seem small. These drugs are aspirin-like drugs with serious side effects like:
- irritation of the digestive tract - extension of coagulation - allergic reactions, such as agranulocytosis which is seen most often after administration of oxyphenylbutazone. Tranexamic acid could have a slight antiphlogistic effect, which is a poorly described property. For further research of inflammatory reactions this may be of importance. The application ofcorticosteroids in a dosage over a period of 4 days is strongly recommended by this study and by the literature. The bad reputation these chemicals have is due to side effects that arise after long-term administration for chronic diseases. Serious side effects like allergic reactions are lacking. Illnesses like epilepsy, glaucoma, hypoparathyroidism and diabetes mellitus can become manifest; the latter two do not occur with short-term use. Absolute contra-indications are formed by an acute virus infection, e.g. herpes or a history of tuberculosis. Relative contra-indications are: stomach ulcer, psychiatric past, serious hypertension, diabetes mellitus, bacterial infections, tendency for thrombosis', young age, pregnancy. In the Department of Oral and Maxillofacial Surgery of the University Hospital in Groningen, we give corticosteroid treatment to all patients who will undergo a surgical removal of the lower third molar. A prescription for an ordinary analgesic will only be given to persons in whom a contra-indication for steroids exists. Because of the costs, there is a preference for prednisolon 32 tablets (5 mg each). Since the drug is to be administered preventively, the patient takes 8 tablets (5 mg each) in the operation room, preceding the removal of the wisdom tooth. The other 24 will be taken at home with written instructions. The intake schedule is as follows: day of operation first day after operation second day after operation third day after operation
4--4--3-3 2-2-2-2 2-2-1-1 1-1-1-1
ORAL SURGERY AND ANTIPHLOGISTICS
Patients undergoing a big elective operation, e.g. osteotomy, are administered betamethasone, according to the following schedule: 8 and 4 mg, in the drip at the beginning and the end of the operation, respectively. 4 and 2 mg, i.m, or orally, in the morning and on the evening of the following day, respectively. - 2 and I mg, respectively as immediately above. I mg in the morning. Antibiotics are given for a week. The clinical impression is positive, which is in agreement with the literature.
Recommendations for further research The aim of a further study could be: to obtain a better insight into the mechanism of the inflammatory reaction; to test the recently developed antiphlogistics (analgesics included) which selectively interfere in the course of the inflammatory mechanism; to improve the measurement of the swelling; to look for an objective measure for the diagnosis of alveolitis; to look for a relation between hormonal status and alveolitis. The comparative study of V AN GOOL 12 already provided a number of questions which, related to the existence of mediators and acute phase proteins, might give insight into the inflammatory reaction: what is the relation between pain, swelling and trismus? why do some patients have swelling, but no pain? why have others pain, but no swelling? why do all patients have trismus? Newly processed drugs must have different targets in the inflammatory reaction than corticosteroids and the now known antiphlogistics. The present anti-rheumatics do not
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differ much in targets and in effects and side effects, although new products are put on the market continually. The mutual relation between mediators, acute phase proteins, stages of the inflammatory reaction and the clinical inflammatory phenomena must be revealed. Also, the influence of drugs and if possible of anti-mediators, not only on mediators, but also on the clinical appearance of the inflammation, should be investigated. It seems possible to improve strongly on measurement of the swelling. Only BREYTENBACH 6 has compared several measuring methods. It is possible to compare the methods used in this experiment with the Scandinavian method in which a bitefork with pins attached to it is used to measure the swelling of the cheek. Application of rasters, of photogrammetric or holographic techniques also deserve attention. If the shape of the face could be determined with the help of a computer, so that after the operation the swelling could be calculated in volume units after subtraction, this would mean a great step forward. Perhaps echography and radar would also be an asset. To establish the relation between the development and the frequency of alveolitis and causative or therapeutic factors, an objective measure for the diagnosis of alveolitis must be found. Measuring the pH of the alveolus or the concentration of a chemical causing the foetide factor may be a possibility. It seems that the model of the patient undergoing a standardized operation like the third molar operative extraction isideally suited for further research.
References 1.
2.
ALBUM, B., et a!.: Bilateral surgical removal of impacted mandibular thirdmolar as a model for drug evaluation: a test with oxyphenbutazone
(Tanderil'['), Int. J. Oral Surg, 1977: 6: 177-189. ANDERSSON, L.: Combined prophylaxis of
haemorrhage and trombosis after prostatectomy. Acta Chir. Scand. 1965: 130: 393-398.
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3. BAZERQUE, P. M., et a!.: Use of indomethacin as an anti-inflammatory agent in patients subjected to exodontia. Rev. Asoc. Odontol. Argent. 1967: 55: 526-528. 4. BEECHER, H. K.: The powerful placebo. J. Am. Med. Assoc. 1955: 159: 1602-1607. 5. BIRN, H.: Etiology and pathogenesis of fibrinolytic alveolitis ("dry socket"). Int. J. Oral Surg, 1973: 2: 211-263. 6. BREYTENBACH, H. S.: Objective measurement of post-operative swelling. Int. J. Oral Surg, 1978: 7: 386-392. 7. BYSTEDT, H.: Clinical and haemotological investigation of Rheumapax'P in surgical removal ofimpacted wisdom teeth from the mandible. Int. J. Oral Surg. 1976: 5: -6-70. 8. DUKES, M. N. G. : Meyler's side effects ofdrugs. A survey of unwanted effects of drugs reported in 1972-1975 (VIII). Excerpta Medica, Amsterdam 1975. 9. GEEL, C.J. E. VAN: Erfahrungen mit Tanderil® in Schweiz. Monatschr. der Kieferchirurgie. Zahnheilkd. 1968: 78: 257-259. 10. GERSEL-PEDERSEN, N.: Tranexamlc acid in alveolar sockets in the prevention of alveolitis sicca dolorosa, Int. J. Oral Surg. 1979: 8: 421-429. 11. GOODMAN, L. S. & A. GILMAN: The pharmacological basis of therapeutics, 6th edition. Mac Millan, New York 1980. 12. GOOL, A. V. VAN: De verstandkies in de onderkaak. Groningen, thesis, 1975. 13. GOOL, A. V. VAN, et a!.: A photographic method of assessing swelling following third molar removal. Int. J. Oral Surg, 1975: 4: 121-129. 14. HALSTRICK, F.: Entwicklung eines photographischen Messverfahrens postoperative Odeme nach Entfernung unterer Weisheitsziihne. (In Verbindung mit einem Doppelblindversuch tiber Tanderile ), Kiel, thesis, 1974. 15. HOOLEY, J. R., et a!. : Betamethasone in traumatic oral surgery. J. Oral Surg, 1969: 27: 398-403.
16. LOKKEN, P., et al.: Bilateral surgical removal of impacted lower third molar teeth as a model for drug evaluation: a test with ibuprofen. Eur. J. Clin. Pharmacol. 1975: 8: 209-216. 17. Martindale, the extra pharmacopoeia. Incorporating Squire's Companion. 27th edition. AINLY WADE et a!. (eds.) London, Pharmaceutical Pr., 1977. 18. PETERSEN, J. K.: Anti-inflammatory and analgetic effects of indomethacin following removal of impacted mandibular third molars. Int. J. Oral Surg. 1975: 4: 267-276. 19. RITZAu, M.: The prophylactic use of tranexamic acid (cyclokapron) on alveolitis sicca dolorosa, Int. J. Oral Surg. 1973; 2: 196--199. 20. RUEDY, J.: A comparison of the analgesic efficacy of naproxen and acetylsalicylic acid-codeine in patients with pain after dental surgery. Scand. J. Rheumatol. 1973: suppl. 2: 60-63. 21. STETSON, J. B., et al.: Analgesic activity of oral naproxen in patients with postoperative pain. Scand. J. Rheumatol. 1973: supp!. 2: 50-55. 22. VARLEY, E.: Control of swelling, trismus and pain after the removal of impacted wisdom-teeth. In: Die posttraumatische Entziindung. Hrsg. von J. Lindner et al. Bern etc., Huber 1976, 237-244. 23. WOOD, G. D., et a!.: A comparison of three methods of measuring maximal opening of the mouth. J. Oral Surg. 1979: 37: 175-177. 24. ZWAN, J. VAN DER: Verstandskies en antiphlogistica. Groningen, thesis 1980.
Address:
J. van der Zwan Department of Oral Surgery University Hospital
Oostersingel Sv 9711 XE Groningen The Netherlands