Br. J. clin. Pharmac. (1992), 33, 395-399

An evaluation of buffered aspirin and aspirin tablets in postoperative pain after third molar surgery R. A. SEYMOUR', M. WELDON2, P. KELLY3, E. NICHOLSON4 & J. E. HAWKESFORD2 'Department of Operative Dentistry, The Dental School, Newcastle upon Tyne, 2Department of Oral and Maxillofacial Surgery, Newcastle General Hospital, Newcastle upon Tyne, 3Department of Medical Statistics and 4 Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne, Newcastle upon Tyne

1 Single doses (500 and 1000 mg) of both buffered aspirin and aspirin tablets were compared with placebo in a randomised double-blind trial of parallel design in patients with postoperative pain after third molar surgery. 2 Only buffered aspirin 500 mg provided significant pain relief (P = 0.016) during the 5 h investigation period. 3 A significant correlation (P = 0.004) was observed between overall pain scores after the various aspirin treatments and aspirin esterase activity. 4 Buffered aspirin preparations afforded a slight advantage over aspirin tablets in the control of postoperative pain after third molar surgery. However, the duration of analgesia was short (approximately 2 h). 5 Aspirin esterase activity appears to be an important determinant of the drug's efficacy in postoperative dental pain.

Keywords buffered aspirin aspirin tablets third molar surgery aspirin esterases

postoperative pain

Introduction

Several studies have shown that aspirin (acetylsalicylic acid, ASA) is an effective analgesic for controlling postoperative pain after third molar surgery (Cooper & Beaver, 1976; Henrikson et al., 1979; Skjelbred, 1984; Von Graffenried et al., 1980). In a series of single dose studies, we have shown that aspirin-induced analgesia in postoperative dental pain is related to dose and formulation (Seymour & Rawlins, 1982; Seymour et al., 1986). On a dose per dose basis, soluble aspirin provided an earlier onset of analgesia than aspirin tablets in the immediate postoperative period after third molar surgery (Holland et al., 1988). We also demonstrated that plasma concentrations of acetylsalicylate correlated with plasma aspirin esterase activity, and both factors were significant determinants of the drug's efficacy (Seymour et al., 1984a). Recently, it has been shown that a new buffered chewable aspirin preparation provides a greater peak concentration of acetylsalicylate when compared with conventional aspirin tablets (Goke et al., 1989). However, it has not been demonstrated whether such a preparation has any advantage over aspirin tablets in an acute pain model. Thus, the aims of the present study were to compare the efficacy of single doses of buffered chewable aspirin (500 and 1000 mg) and aspirin tablets (500 and 1000 mg)

in patients with postoperative pain after third molar surgery, and to investigate the relationship between efficacy and plasma aspirin esterase activity.

Methods

One hundred and eighty-two patients (123 females) who required the removal of their impacted third molars agreed to participate in the study, which had received prior ethical approval from the Joint Health Authority and University Ethics Committee. Informed written consent was obtained from all patients in accordance with the Declaration of Helsinki, 1975. The patients were recruited from the waiting list of the Department of Oral Surgery and had been admitted for routine removal of all their third molars. Prior to surgery, a 10 ml venous blood sample was taken for determination of plasma aspirin esterase activity, which was measured as previously described (Seymour et al., 1984b). Plasma aspirin esterase activity was expressed as nmol of salicylate formed per ml of plasma per minute (nmol salicylate ml-' min-'). Third molar surgery was carried out under general anaesthesia. All patients were premedicated with oral

Correspondence: Dr R. A. Seymour, Department of Operative Dentistry, The Dental School, Newcastle upon Tyne

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temazepam 10 mg and intramuscular atropine 0.6 mg at 2 h and 30 min respectively before surgery. Anaesthesia was induced with 4-6 ml of thiopentone 2-5% w/v and muscle relaxation was achieved with intravenous suxamethonium 75-100 mg. A mixture of nitrous oxide, oxygen and enflurane was used to maintain anaesthesia. The third molars were removed by a standard technique and, where necessary, bone removal was carried out with a drill under saline spray. Operating time (in min) was recorded from first incision to completion of last suture. On completion of surgery, patients were returned to the ward and time was allowed for them to recover from the effects of the general anaesthetic. In this early postoperative period, patients recorded their pain intensity on 100 mm visual analogue scales (VAS). The boundaries of the scale were marked 'no pain' and 'unbearable pain' When pain was recorded at a level greater than 30 mm on the VAS, and/or when it reached an intensity such that an analgesic was requested, the patients were entered into the study. They received in random, double-blind order, either a single dose of buffered aspirin (500 or 1000 mg), a single dose of aspirin tablets (500 or 1000 mg), or matched placebo. To ensure double-blind conditions, the double-dummy technique was used. That is, each patient received two chewable tablets and two tablets to swallow. Between 35-38 patients were allocated to each treatment group. Randomisation ensured that in each treatment group, there were the same proportions of males to females. Drug administration, and the explanation of the VAS was carried out by the same nurse/observer on all occasions. Patients continued to register their pain experience on serial, vertical VAS at 0, 15, 30, 45, 60, 90, 120, 180, 240 and 300 min after dosage. Pain recordings for each patient were collated to form a graph of pain against time and the area under the graph measured using the trapezoidal method. Such a measure (AUEC(0,300)), expressed in units of mm h gives an overall integrated value of each patient's pain experience throughout the 5 h investigation period (Matthews et al., 1990). During the study, patients were permitted to take escape analgesics (Co-codamol 1 g). For those patients who took escape analgesics, the time of dosage was recorded, and their previous VAS recording extrapolated at this level for all subsequent time points (Lasagna,

different levels of these covariates and compared using the pooled s.d. from the ANOVA table as described by Armitage & Berry (1987). These adjusted means are also reported in Table 1. Analysis of covariance was also used to examine the relationship between AUEC-(0,300) after the various aspirin treatments and plasma aspirin esterase activity. The comparisons of the median time to taking escape analgesics between each of the treatment groups and the placebo are based upon the log rank test. Differences between treatment groups for patients' overall assessment of pain relief were assessed using chi-square tests. Results A synopsis of the patients and operative variables together with the efficacy data are shown in Table 1. Mean pain scores for each time point for the two doses of buffered and aspirin tablets with respect to placebo are shown in Figures la and b. Overall pain

a

E E 0

0

0

b

a-E

CL

1980). At the end of the investigation period, patients were asked to complete a 5-point global scale which evaluated their overall pain relief from the medication. The categories of the scale were: very effective, effective, good, moderate and poor.

Statistical analysis The mean AUEC(0,300) measurements for each treatment were compared using a one-way analysis of covariance with sex, age, weight, baseline pain, operating time, escape analgesia (whether or not an escape analgesic was taken during the investigation period) and plasma aspirin esterase as covariates. Of these, age, baseline pain, escape analgesia were significant (all P < 0.01). Hence the treatment means were adjusted for the

0

1

2

3

4

Time (h) Figure 1 a) Mean pain scores (mm + s.e. mean) after treatment with placebo (0), aspirin tablets 500 mg (P. aspirin, *) and buffered aspirin 500 mg (B. aspirin, A). b) Mean pain scores (mm + s.e. mean) after treatment with placebo, aspirin tablets 1000 mg (P. aspirin) and buffered aspirin 1000 mg (B. aspirin).

Aspirin after third molar surgery

397

Table 1 Patient, operative and efficacy variables for each treatment group

Number of patients Males:Females Age (years ± s.d.) Weight (kg ± s.d.) Operating time (min ± s.d.) Baseline pain scores (mm) on 100 mm VAS ± s.d. Overall pain scores (AUEC(0,300))mmh ± s.e. mean Overall adjusted pain scores (AUEC(0,300))mmh ± s.e. mean Patients taking escape analgesics Y: N Median time to escape analgesia (min) Plasma aspirin esterase activity (nmol ml-1 min-') ± s.d.

Placebo

Buffered aspirin 500 mg

Aspirin tablets 500 mg

Buffered aspirin 1000 mg

Aspirin tablets 1000 mg

37 11: 26 26.1 ± 7.1 62.2 ± 11.9 24.5 ± 11.4

35 12: 23 25.2 ± 5.4 66.4 ± 13.6 21.3 ± 9.8

35 11 24 25.5 ± 8.4 65.2 ± 10.8 23.7 ± 12.1

38 11: 27 25.1 ± 6.3 64.8 ± 10.5 20.1 ± 14.7

37 14: 23 28.2 ± 8.5 65.4 ± 9.7 28.5 ± 13.1

53.8 ± 17.1

50.3 ± 19.5+

61.4 ± 19.2+

58.3 ± 19.3+

51.0 ± 19.3

207.7

18.5

134.6 ± 17.5*

202.5 ± 21.7

165.6 ± 18.3

181.6 + 22.3

198.7 + 14.5

147.1 ± 14.9*

189.9 ± 14.9

167.7 ± 14.4

188.7 + 14.5

33: 4

30: 5

25: 10

28: 10

30: 7

70

135*

100*

135*

95

111.0 ± 22.4

103.6 ± 24.7

111.8 ± 24.9

103.0 ± 27.1

106.0 ± 34.9

+Significant difference between groups (P < 0.05). *Significant difference from placebo (P < 0.05). Table 2 Distribution of overall assessment scores for pain relief for the different treatment groups

Very effective and effective Good Moderate to poor Not recorded

Placebo

Buffered aspirin 500 mg

Aspirin tablets 500 mg

Buffered aspirin 1000 mg

Aspirin tablets 1000 mg

8 6 21 2

14 6 14 1

8 3 23 1

16 8 14

10 3 22 2

-

Pooled Buffered vs Plain, P = 0.006. Pooled Buffered vs Placebo, P = 0.09.

scores as assessed by AUEC(0,300) are shown in Table 1. Only patients treated with buffered aspirin 500 mg experienced significantly less pain (P = 0.016) than the placebo group. A high proportion of patients in the present study required escape analgesics during the 5 h investigation period. However, patients in the placebo group required their escape analgesics at an earlier time than those who received either buffered aspirin treatments or aspirin tablets 500 mg. Patients overall assessment of the pain relief afforded by the different treatments is shown in Table 2. There was no significant difference between individual treatment groups. Patients treated with buffered aspirin were more satisfied with their pain relief than those treated with aspirin tablets (P = 0.006), and to a lesser extent than those treated with placebo (P = 0.09). Analysis of covariance showed no significant differences for plasma aspirin esterase activity between treatment groups (P = 0.2 for equal slopes across groups) and hence data for esterase activity and AUEC(0,300) after the various aspirin treatments were pooled. Linear regression analysis of the pooled data (YAUEC

= 79 + 0.93 xesterase) showed a significant relationship (P = 0.004) between the two variables.

Discussion

Although there are many different types of aspirin preparations available to the public, there are relatively few comparative efficacy studies. In previous singledose studies, we have shown that soluble aspirin provided an earlier onset and more prolonged analgesia than the corresponding dose of aspirin tablets in patients with postoperative pain after third molar surgery (Holland et al., 1988; Seymour et al., 1986). Differences in efficacy were attributed to the earlier and greater peak concentrations of ASA after soluble aspirin than after tablets (Levy, 1965; Rance et al., 1975). The findings from the present study in part support this hypothesis. The two doses of buffered aspirin provided slightly better pain relief than aspirin tablets. Also, the pain/time curves during the first hour of the investi-

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gation period (Figures la, b) suggest that the buffered aspirin preparations provided a more rapid reduction in pain than the corresponding doses of aspirin tablets. However, a further study will be required to substantiate this finding, since onset of efficacy was not an aim of the present investigation. The overall pain scores (AUEC(0,300)) after both doses of aspirin tablets were not significantly different from placebo. Using a similar methodology, we have previously shown aspirin tablets 600-900 mg afforded little pain relief when compared with the same doses of soluble aspirin (Holland et al., 1988). The anomaly in the present study is the poor efficacy of buffered aspirin 1000 mg when compared with buffered aspirin 500 mg. Baseline pain scores in this group of patients were significantly higher than those treated with buffered aspirin 500 mg (Table 1). These higher pain scores may have altered the patient's pain sensitivity, which in turn have increased their pain perception and awareness. Such factors could have contributed to the poor efficacy of buffered aspirin 1000 mg in this treatment group. A very high proportion of patients in this study required escape analgesia during the 5 h investigation period, and the numbers were similar for each treatment group. This finding often reflects the clinical situation. However, the analysis has taken this factor into account in two ways. Firstly, the analysis of covariance compares the mean AUEC(0,300) adjusted for significant covariants, of which taking escape analgesics is one such covariant. Secondly, survival analysis of time to escape is of clinical relevance since it is an indication of efficacy and duration of action. The time to escape was significantly longer after the two buffered doses and

after aspirin tablets 500 mg. This would suggest that either the efficacy of the drug was unsatisfactory with a poor duration of action, and/or the inadequate analgesia is due to an increasing pain intensity. Most patients after third molar surgery experience their most severe pain in the early postoperative period (i.e. first 12 h) (Seymour et al., 1985). A further study has shown that pain intensity reaches a maximum 4-5 h after completion of surgery (Fisher et al., 1988). This time point coincides with the median time for escape analgesia in the active treatment groups. Thus, for effective pain control after third molar surgery, it would be appropriate to dose such patients further at this time. Aspirin esterase activity appears to be an important determinant of the plasma concentrations of ASA and the drug's efficacy in postoperative dental pain (Seymour et al., 1984a, 1986). The significant correlation between AUEC(0,300) and aspirin esterase activity continues to support this finding. Thus, patients who metabolise aspirin slowly obtain more pain relief than those who metabolise the drug quickly. It has not been established whether it is possible to titrate a dose of aspirin to an individual's esterase activity. We can conclude from this study that buffered aspirin preparations have a slight advantage over aspirin tablets in the control of postoperative pain after third molar surgery, but the duration of analgesia provided by this type of aspirin is short (approximately 2 h). Aspirin esterase activity is an important determinant of analgesic efficacy after third molar surgery. The authors are grateful to Bayer AG for their generous financial support of this study.

References Armitage, P. & Berry, G. (1987). In Statistical methods in medical research (2nd edition). Oxford: Blackwell Scientific Publications. Cooper, S. A. & Beaver, W. T. (1976). A model to evaluate mild analgesics in oral surgery. Clin. Pharmac. Ther., 20, 241-250. Fisher, S. E., Frame, J. W., Rout, P. G. J. & McEntegart, D. J. (1988). Factors affecting the onset and severity of pain following the surgical removal of unilateral impacted third molar teeth. Br. Dent. J., 164, 351-354. Goke, B., Schmitz-Moorman, P., Boehme, K., Lange, K. & Arnold, R. (1989). Magenvertraglichkeit von Acetylsalicylsaure bei Zusatz von Calciumcarbonat. Eine Studie in Zwei-Behandlungen. Med. Klin., 84, 474-478. Henrikson, P. A., Tjerneberg, A., Ahlstrom, U. & Peterson, L. E. (1979). Analgesic efficacy and safety of Fenbufen following surgical removal of a lower wisdom tooth: a comparison with acetylsalicylic acid. J. int. med. Res., 7, 107-116. Holland, I. S., Seymour, R. A., Ward-Booth, R. P., Lim, K. L. M. & Hoare, R. C. (1988). An evaluation of different doses of soluble aspirin and aspirin tablets in postoperative dental pain. Br. J. clin. Pharmac., 26, 463-468. Lasagna, L. (1980). Analgesic methodology: A brief history and commentary. J. clin. Pharmac., 20, 373-400. Levy, G. (1965). Aspirin absorption rate and analgesic effect.

Anaesth. Analg., 44, 837-841. Matthews, J. N. S., Altman, D. G., Campbell, M. J. & Royston, P. (1990). Analysis of serial measurements in medical research. Br. med. J., 300, 230-235. Rance, M. J., Jordan, B. J. & Nichols, J. D. (1975). A simultaneous determination of acetylsalicylic acid, salicylic acid and salicylamide in plasma by gas liquid chromatography. J. Pharm. Pharmac., 27, 425-429. Seymour, R. A., Meechan, J. & Blair, G. S. (1985). An investigation into postoperative pain after third molar surgery under local anaesthesia. Br. J. Oral Maxillofac. Surg., 23, 410-418. Seymour, R. A. & Rawlins, M. D. (1982). The efficacy and pharmacokinetics of aspirin in postoperative dental pain. Br. J. clin. Pharmac., 13, 807-810. Seymour, R. A., Williams, F. M., Luyk, N. M., Boyle, M. A., Whitfield, P. M., Nicholson, E., Ward-Booth, P. & Rawlins, M. D. (1986). Comparative efficacy of soluble aspirin and aspirin tablets in postoperative dental pain. Eur. J. clin. Pharmac., 30, 495-498. Seymour, R. A., Williams, F. M., Oxley, A., Ward, A., Fearns, M., Brigham, K., Rawlins, M. D. & Jones, P. (1984b). A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time. Eur. J. clin. Pharmac., 26, 567-571. Seymour, R. A., Williams, F. M., Ward, A. & Rawlins,

Aspirin after third molar surgery M. D. (1984a). Aspirin metabolism and analgesic efficacy in postoperative dental pain. Br. J. clin. Pharmac., 17, 697-701. Skjelbred, P. (1984). The effects of acetylsalicylic acid on swelling, pain and other events after surgery. Br. J. clin. Pharmac., 17, 379-384.

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(Received 25 October 1991, accepted 5 December 1991)

An evaluation of buffered aspirin and aspirin tablets in postoperative pain after third molar surgery.

1. Single doses (500 and 1000 mg) of both buffered aspirin and aspirin tablets were compared with placebo in a randomised double-blind trial of parall...
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