Anaesthesia, 1991, Volume 46, pages 828-832
A comparison of azapropazone and aspirin for pain relief following dental extractions
M. A . GARRIOCH, G . J . WARDALL
AND
W. FITCH
Summary Eighty patients received one of three treatments after elective dental surgery involving muIt@le extractions. Group A received aspirin 600 mg, group B azapropazone 300 mg and group C azapropazone 600 mg. AN drugs were administered in a double-blind fashion. Quality of analgesia was unsatisfactory for all treatments; over 30% of patients required supplementary analgesia with an opioid. In addition there were a large number of withdrawals from the study. There were no signgcant differences in analgesic eficacy between groups.
Key words Analgesics; aspirin, azapropazone. Surgery; dental.
The pain associated with multiple extractions and other surgical procedures in the mouth provides a useful model with which to study the analgesic properties of peripherally acting analgesics and anti-inflammatory drugs. There are several reasons for this. The intensity of the pain is sufficient to permit a meaningful assessment of analgesia per se, there is considerable associated soft tissue swelling and trismus, and it is easy to obtain a large number of otherwise healthy individuals who are willing to take part in such a study.' Prostaglandins (notably PGE,, PGF,,, and prostacyclin) appear to have a role in mediating pain by sensitising peripheral pain receptors to mechanical and chemical In addition, a central component has been described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to act mainly by inhibiting the enzyme cyclo-oxygenase and thus prevent the synthesis of prostaglandin. Azapropazone is a pyrazole-derived NSAID used widely in the treatment of rheumatic conditions. It has analgesic, anti-inflammatory, antipyretic and uricosuric proper tie^;^.' however, few data exist as to the efficacy of this drug for postoperative analgesia. The objectives of this study were
to evaluate this aspect of its pharmacological profile; to determine, to a limited extent, the dose-response relationship of the drug, and to compare the actions of azapropazone with those of a standard analgesic, namely aspirin.
Methods Eighty-six patients, male or female, aged 18 to 50 years, who were ASA grade 1 or 2 and scheduled to undergo elective oral surgery involving multiple extractions were entered into the study. No patient was included who had known hypersensitivity to NSAIDs, had a history of peptic ulceration or gastrointestinal bleeding, had received medication with NSAIDs or opioids in the 24 hours before operation, had any bleeding disorder or who required anticoagulant therapy. Patients were also not studied if they were unable to follow the design of the study or give informed patient consent. Ethics committee approval and informed patient consent were obtained. A standard anaesthetic technique was employed. Premedication was with temazepam 20 mg (patient weight < 50 kg) or 30 mg (patient weight > 50 kg), given by mouth 1.5 to 2 hours before operation. Anaesthesia was
M. A. Garrioch,* MB, ChB, FCAnaes, G. J. Wardall,? BSc, MB, ChB, FCAnaes, Registrars, W. Fitch, BSc, MB, ChB, PhD, FCAnaes, FRCP(G), Professor, University Department of Anaesthesia, Glasgow Royal Infirmary, Glasgow G3 1 3ER, Scotland. Correspondence to Dr M.A. Garrioch, c/o Professor W. Fitch please. * Current address: Department of Shock Trauma, Washington Hospital Center, 110 Irving Street, N.W., Washington DC, 20010 USA. Current address: Department of Anaesthesia, Green Lane Hospital, Auckland, New Zealand. Accepted 18 July 1990. 0003-2409/91/100828 +05 $03.00
@ 1991 The Association of Anaesthetists of Gt Britain and Ireland
828
829
Comparison of azapropazone and aspirin induced with thiopentone 5 mg/kg and neuromuscular blockade obtained with vecuronium 0.1 mg/kg. Nasotracheal intubation was performed and a throat pack inserted. Anaesthesia was maintained with nitrous oxide and enflurane in oxygen, supplemented by fentanyl 1 pg/kg every 30 minutes. The patients’ lungs were ventilated mechanically. Residual neuromuscular blockade was antagonised with neostigmine 2.5 mg plus glycopyrronium 0.5 mg. Electrocardiogram and arterial pressure were monitored noninvasively throughout the procedure. At the conclusion of surgery patients were transferred to the recovery room where they were questioned at 15 minute intervals about their pain. Treatment of any pain was provided in one of three groups A, B or C as outlined below. The study drug was administered by mouth on a doubleblind and randomised basis when the patient first complained of pain in the postoperative period, provided that this occurred within the first 4 postoperative hours. Group A received aspirin 600 mg, group B azapropazone 300 mg, and group C azapropazone 600 mg. Morphine 10 mg was given intramuscularly as a rescue analgesic if adequate pain relief was not obtained within 90 minutes of administration of the drug. If supplementary analgesia was required because of the return of pain after initially adequate analgesia, paracetamol 1 g was given by mouth. Pain was assessed using a 10 cm visual analogue scale (VAS) and by a four-point ordered-category scale as follows; 0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain. The degree of postoperative trismus was assessed by determining the extent of mouth opening (measured as the distance between upper and lower incisors on full opening of the mouth, using metal calipers) and noting any changes in measurements postoperatively. Assessments were carried out at the time of first request for analgesia time 0, and at 0.5, 1, 2, 4, 6 and 8 hours thereafter, and finally on the morning of the following day. Mouth opening was assessed before operation in addition to the above times. Patients who were withdrawn from the study were recorded as such, together with the reason for their withdrawal. The need for additional analgesia was noted, as was any evidence of postoperative haemorrhage and the occurrence of any other side effects. Venous blood samples (10 ml) were taken for azapropazone assay from 17 patients in group B and 20 in group C at 30 minutes and at 1, 2, 4, 6 and 8 hours. Azapropazone concentrations were analysed using a modification of that method described by Farrier.24 This analysis was used to avoid interference by paracetamol. The method is linear to above 100 pg/ml. The coefficient of variance was at 10 pg/ml 4.9%, and at 50 pg/rnl 3.8%. Recoveries were better than 95%. Statistical significance for any differences between treatments was taken as p < 0.05. Data were assessed for suitability for parametric analysis of variance (ANOVAR). Sex, use of rescue and supplementary analgesia, numbers of withdrawals and incidence of side effects were assessed by Chi-squared tests. Mouth opening and VAS pain scores were assessed by one-way analysis of variance at each time of measurement, and further compared by covariant analysis; the covariate was the pre-induction and baseline (T = 0) values for mouth opening, and the baseline values for VAS. Category pain scores were assessed initially by
Table 1. General patient description, mean (SD) Ages; years Group A (n = 29) Group B (n = 24) Group C (n = 28)
24.4 23.2 26.0
(5.7) (5.4)
(7.1)
Weight; kg Group A (n = 29) Group B (n = 25) Group C (n = 26)
(10.1)
63.9 59.6 65.1
(10.1) (11.4)
Females
Males ~~
Group A Group B Group C
20 19 22
8 5 6
Chi-squared tests at each time point, and subsequently changes from the baseline value were analysed in a similar manner. Where treatment differences were indicated by the analysis of variance and covariance, these were tested further using Duncan’s multiple range test. Results
Six patients did not require analgesia during the first 4 hours after operation and therefore did not contribute to the results of the study. Of the remaining 80 patients, 28 received aspirin 600 mg (group A), 24 azapropazone 300 mg (group B) and 28 azapropazone 600 mg (group C). There were no significant differences between the groups with regard to age, sex and weight distribution (Table I), initial baseline pain score, and extent of surgery. The mean time of study drug administration was 30.5 minutes after awakening. Thirty-seven percent of patients who requested analgesia did so immediately on awakening; 70% of patients had received study medication within the first postoperative hour and 97% within 90 minutes. Analysis of variance for pain scores (Fig. 1) indicated significant treatment differences at one hour after administration only; group B had a significantly lower mean score than group C. Group A was intermediate between the other groups and did not differ significantly from either. Analysis of covariance indicated significant effects of the initial (T = 0) value at 0.5, 1, 2 and 8 hours only and significant treatment differences at one hour only; group B had a significantly lower mean score than groups A or C. 60 r 50
ld n 1
4 Time (hours)
6
0
Fig. 1. Visual analogue scale (mm) after the operation
2
4
(m, aspirin;
B, azapropazone 300 mg; 0 , azapropazone 600 mg).
M . A . Garrioch, G . J. Wardall and W. Fitch
830
Table 2. Pain score frequencies. ~~
Time
Score
0 hours
Group A Group B Group C
GroupA Group B GroupC GroupA Group B Group C GroupA Group B Group C
0.5 hours
1 hour
2 hours
4 hours
Group A Group B GroupC GroupA
6 hours
Group B
Group C GroupA Group B Group C Group A Group B GroupC
8 hours
24 hours
0 0
Chi-squared
d.f.
P
4.826
4
ns
1 0
1 2 3 11 12 5 5 8 9 5 13 9
0 1 1
10 7 5
12 6 11 5 14 7
1.347
4
ns
2 3 0
12 9 3 9 8 0 10 13 3
6.963
6
ns
3 4 2
16 12 13
5 2 6
1 1 1
2.280
4
ns
8 7 3
11 5 16
5 0 5 1 2 0
9.685
4
< 0.05
11
7 7 13
4 0 3 0 0 0
6.387
4
ns
7 8 8 7 6
13 6 9
0 0 1 0 2 0
0.766
2
ns
14 10 17
7 7 3
0 0 0 0 0 0
3.296
2
ns
Table 3. Use of rescue analgesia (intramuscular morphine).
Group
Number of patients needing rescue
Time of rescue; minutes, mean (SD) range
A
9 10 11
59 (41) 20-150 53 (33) 15-125 74 (40) 32-180
B C
Assessment of the ordered category pain scores (Table 2 ) at each time point indicated significant differences at 4 hours only; these differences were largely because of the increased frequency of patients scoring one in group C compared to other groups. Analysis of change from the zero time score showed no significant differences between the three groups at any time. 40
-
35
E
-Em 30 5 c a W
5 25
9 20
Before operation
0
0.5
I
2 4 Time (hours)
6
8
Fig. 2. Mouth opening (mm) before and after the operation (m, aspirin; B, azapropazone 300 mg; azapropazone 600 mg).
n,
n 8 10
11
ANOVAR for mouth opening data (Fig. 2 ) indicated significant treatment differences at one and two hours after drug administration; group C had significantly lower mean mouth opening than A or B. Analysis for covariance indicated significant effects of the TO value at all times following drug administration, but no effect on the preinduction value. Analysis of covariance was thus repeated using only the baseline TO value as covariate and this analysis indicated significant differences at T1 only; again group C had a significantly lower mean mouth opening than A or B. Supplementary analgesia with paracetamol 1 g was provided for 18 patients (64%) in group A, 14 (58%) in group B and 15 (53%) in group C. There were no significant differences between groups. Rescue analgesia was needed for 30 patients (Table 3). There were no significant differences between groups either in numbers of patients requiring such analgesia or in the times at which it was administered. Nineteen patients were withdrawn from the study (Table 4). Of these, 13 withdrawals had inadequate pain relief, even after intramuscular morphine, and six had difficulties with blood sampling or were uncooperative. No significant differences were found between the number withdrawn in each group. Table 5 gives side effects as volunteered by patients.
Comparison of azapropazone and aspirin
831
Table 4. Patients withdrawn from the study. Group
A B C
Number withdrawn Remaining Chi-squared d.f. p 5 7
0.95
23 17 21
7
2
ns C
Withdrawn for 'inadequate pain relief (n) A B C
0
z 30t
0
3 5 5
There were no significant differences between groups. Mean plasma azapropazone levels are shown in Fig. 3 .
3
2
4
5
I
I
I
6
7
8 0
Time (hours)
Plasma azapropazone concentrations (pgiml) after administration of azapropazone 300 mg and azapropazone 600 mg ( 0 ,azapropazone 300 mg; *, azapropazone 600 mg).
Fig. 3.
Discussion Several previous s t ~ d i e s l ,attest ~ . ~ to the efficacy of orally administered nonsteroidal anti-inflammatory drugs in relieving the pain associated with oral surgery. It is therefore surprising that the main finding of the present study was the disappointing quality of analgesia obtained in all treatment groups. Approximately one third of the patients required the administration of a rescue opioid and a further number were withdrawn when analgesia was considered inadequate, despite the administration of 10 mg morphine. Theoretically, this situation must have arisen because the pain associated with oral surgery was much more severe than anticipated thus it should have been treated with potent analgesics ab initio; the drugs employed in the investigation did not possess adequate analgesic properties; the time of drug administration was inappropriate or a combination of all of these. There is no doubt that the pain experienced by the patient, as indicated by the high initial visual analogue scores, was severe before they requested an analgesic. The day-to-day practice of anaesthesia demonstrates clearly that the control of pain is much easier if an analgesic is administered before the pain becomes severe." Pain is a subjective phenomenon; nevertheless, the relatively unsatisfactory nature of the analgesia obtained in this study may have been due, in part at least, to the stoical nature of the patients; the request for analgesia only occurred once the pain had already become intense. In this context, it may be relevant to note that most of the previous studies on the analgesic efficacy of NSAIDs were carried out in North America and it is conceivable that earlier requests for pain relief yielded more satisfactory results. Another factor which may be considered is that previous studies were carried out by nonanaesthetists, notably clinical pharmacologists and oral surgeons. It may be that these investigators have a different perception as to what constitutes satisfactory postoperative analgesia. They may also be less willing to administer potent opioid analgesics because of concern about side effects.
The drugs used in the study do undoubtedly possess analgesic properties. Aspirin has been used extensively in the treatment of mild to moderate pain.5,R-'0.'4 Azapropazone has been used for some time for the treatment of rheumatic conditions and a large number of studies attest to its analgesic efficacy for this purpose.18-20 However, certain questions remain unanswered. We are at a loss to explain why no difference in plasma levels of azapropazone 300 mg and 600 mg doses was shown. In fact all previous work investigating azapropazone has assessed the drug by analgesic activity i.e., ability to modify pain threshold, not by measurement of plasma levels.23Thus we believe our work to be the first to compare plasma level with analgesic effect. Work previously done in healthy human volunteer^'^ indicates that peak plasma levels of azapropazone occur about 90 minutes after administration, thus we were disappointed to find that this did not occur in our study. The timing and method of drug administration was also shown to be inappropriate because postoperative plasma drug concentrations were so low they gave minimal analgesia. It should also be noted that a high degree of variability exists in these postoperative plasma concentrations; some patients had only traces of azapropazone in the blood up to 4 hours after administration, whereas in a small minority concentrations were surprisingly high. There are several possible explanations for this. Gastric emptying may well have been markedly reduced because of the pain experienced by some patients. Another theory is that the administration of opioids during the operation inhibited the entry of drug into the duodenum thus slowing absorption, although recent workz2 suggests that fentanyl may not have this effect. In retrospect, it would have been useful to measure the postoperative concentrations of aspirin to reinforce these findings, but unfortunately this was not done. Previous studies of a similar nature did not include measurement of
Table 5. Side effects. ~
Group A B C
_____
~~
None
Nausea
Headache
Sore throat
Bleeding
Other
18 19 18
4
1
2
3 3
1 2
1
2 0 2
1 0
0
1
832
M . A . Garrioch. G . J. Wardall and W . Fitch
plasma drug concentrations a n d thus cannot aid our conclusions. In conclusion, this study, in contrast to previous work, shows that NSAIDs given orally are not an efficacious means of providing analgesia in a large number of patients following dental extractions. We believe that the subject warrants further study by anaesthetists, since they are often involved in the initial prescription of postoperative analgesia for such patients. Our findings do highlight the importance of achieving, a n d verifying, therapeutic concentrations of such drugs (particularly after oral administration) before drawing conclusions on analgesic efficacy.
References 1. COOPERSA. Five studies on ibuprofen for postsurgical dental
pain. The American Journal of Medicine 1984; 11: 70-7. RJ, MONCADA S, VANEJR. Analgesic, antipyretic and 2. FLOWER anti-inflammatory agents; drugs employed in the treatment of AG, GOODMAN LS, RALLTW, MIVADF, gout. In: GILMAN eds. The pharmacological basis of therapeutics. New York: Macmillan, 1985: 674-715. 3. SEYMOUR RA. Use of analgesics in postoperative dental pain; a review. Journal of the Royal Society of Medicine 1984; 17: 949-54. SH. Peripheral analgesia; mechanism of the 4. FERREIRA analgesic action of aspirin like drugs and opiate-antagonists. British Journal of Clinical Pharmacology 1980; 1 0 237s-45s. 5. HIGGS GA. Arachidonic acid metabolism, pain and hyperanalgesia; the mode of action of non-steroid mild analgesics. British Journal of Clinical Pharmacology 1980; 10: 233s-5s. 6. NICKARDERR. Non-steroidal anti-inflammatory agents. Annual Review of Pharmacology and Toxicology 1979; 1 9 469-90. 7. REYNOLDS JEF, ed. Martindale-the extra pharmacopoeia. London: Pharmaceutical Press, 1989: 9. HT, LASAGNA L, GILLIES 8. CALIMLIM JF, WARDELL WM, DAVIS AJ. Analgesic efficacy of an orally administered combination of pentazocine and aspirin. Clinical Pharmacology and Therapeutics 1977; 21: 34-43. JA, WHITE RW, WHITE EH, HUGHESMK. An 9. FORBES evaluation of the analgesic efficacy of proquazone and aspirin in post-operative dental pain. Journal of Clinical Pharmacology 1980; 2 0 465-74.
10. OKUN R, GREEN JW, SHACKELFORD RW. An analgesic comparison study of indoprofen verses aspirin and placebo in surgical pain. Journal of Clinical Pharmacology 1979; 19 487-92. 11. SCOTTR, ELLISE, UPTONLG. Double-blind evaluation of etodolac (200 mg, 400 mg) compared with zomepirac (100 mg) and placebo on third molar extraction pain. Oral Surgery, Oral Medicine and Oral Pathology 1986; 6 2 63842. 12. MEHLISCHDR, JOY ED. Zomepirac sodium vs APC with codeine for oral surgery pain. Journal of Oral Surgery 1981; 3 9 426-9. JK. Diflusinal, a new analgesic, in the treatment of 13. PETERSEN postoperative pain following removal of impact mandibular third molars. International Journal of Oral Surgery 1979; 8 102-1 3. 14. COOPERSA. Comparative analgesic efficacies of aspirin and acetaminophen. Archives of Internal Medicine 1981; 141: 282-5. 15. LEACHH. The determination of azapropazone in blood plasma. Current Medical Research and Opinion 1976; 4: 3543. 16. GILLIESGWA, KENNYGNC, BULLINGHAM RES, MCARDLE CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral, non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 4 2 727-31. JMG, WEDLEYJR, ADAMS 17. JONESRM, CASHMAN JN, FOSTER AP. Comparison of infusions of morphine and lysine acetyl salicylate for the relief of pain following thoracic surgery. British Journal of Anaesthesia 1985; 57: 259-63. 18. HINGORANIK . A comparative study of azapropazone and ibuprofen in the treatment of osteoarthrosis of the knee. Current Medical Research and Opinion 1976; 4:57-64. AJM, MOLLJMH, HORTJF. A comparison of three 19. FRANK ways of measuring pain. Rheumatology and Rehabilitation 1982; 21: 211-7. 20. KEANWF, KRAAGGR, ROONEYPJ, CAPELLHA. Clinical therapeutic trial of aspirin and azapropazone in rheumatoid arthritis when prescribed singly and in combination. Current Medical Research and Opinion 1981; I: 164. or relief! 21. ARMITAGEEN, Postoperative pain-prevention British Journal of Anaesthesia 1989; 63: 136-8. K, ANDREASEN F, 22. SCHURIZEK BA, WILLACYLA, KRAGLUND JUHL B. Antroduodenal motility, pH and gastric emptying during balanced anaesthesia; comparison of pethidine and fentanyl. British Journal of Anaesthesia 1989; 6 674-82. 23. GABKA J. The dose dependent analgesic effect of intravenously administered azapropazone. Clinical Trials Journal 1983; 2 0 219-230. DS. Re: Analysis of azapropazone. Arzneim-Forsch. 24. FARRIER 1974: 24: 747.
A comparison of azapropazone and aspirin for pain relief following dental extractions
M. A . GARRIOCH, G . J . WARDALL
AND
W. FITCH
Summary Eighty patients received one of three treatments after elective dental surgery involving muIt@le extractions. Group A received aspirin 600 mg, group B azapropazone 300 mg and group C azapropazone 600 mg. AN drugs were administered in a double-blind fashion. Quality of analgesia was unsatisfactory for all treatments; over 30% of patients required supplementary analgesia with an opioid. In addition there were a large number of withdrawals from the study. There were no signgcant differences in analgesic eficacy between groups.
Key words Analgesics; aspirin, azapropazone. Surgery; dental.
The pain associated with multiple extractions and other surgical procedures in the mouth provides a useful model with which to study the analgesic properties of peripherally acting analgesics and anti-inflammatory drugs. There are several reasons for this. The intensity of the pain is sufficient to permit a meaningful assessment of analgesia per se, there is considerable associated soft tissue swelling and trismus, and it is easy to obtain a large number of otherwise healthy individuals who are willing to take part in such a study.' Prostaglandins (notably PGE,, PGF,,, and prostacyclin) appear to have a role in mediating pain by sensitising peripheral pain receptors to mechanical and chemical In addition, a central component has been described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to act mainly by inhibiting the enzyme cyclo-oxygenase and thus prevent the synthesis of prostaglandin. Azapropazone is a pyrazole-derived NSAID used widely in the treatment of rheumatic conditions. It has analgesic, anti-inflammatory, antipyretic and uricosuric proper tie^;^.' however, few data exist as to the efficacy of this drug for postoperative analgesia. The objectives of this study were
to evaluate this aspect of its pharmacological profile; to determine, to a limited extent, the dose-response relationship of the drug, and to compare the actions of azapropazone with those of a standard analgesic, namely aspirin.
Methods Eighty-six patients, male or female, aged 18 to 50 years, who were ASA grade 1 or 2 and scheduled to undergo elective oral surgery involving multiple extractions were entered into the study. No patient was included who had known hypersensitivity to NSAIDs, had a history of peptic ulceration or gastrointestinal bleeding, had received medication with NSAIDs or opioids in the 24 hours before operation, had any bleeding disorder or who required anticoagulant therapy. Patients were also not studied if they were unable to follow the design of the study or give informed patient consent. Ethics committee approval and informed patient consent were obtained. A standard anaesthetic technique was employed. Premedication was with temazepam 20 mg (patient weight < 50 kg) or 30 mg (patient weight > 50 kg), given by mouth 1.5 to 2 hours before operation. Anaesthesia was
M. A. Garrioch,* MB, ChB, FCAnaes, G. J. Wardall,? BSc, MB, ChB, FCAnaes, Registrars, W. Fitch, BSc, MB, ChB, PhD, FCAnaes, FRCP(G), Professor, University Department of Anaesthesia, Glasgow Royal Infirmary, Glasgow G3 1 3ER, Scotland. Correspondence to Dr M.A. Garrioch, c/o Professor W. Fitch please. * Current address: Department of Shock Trauma, Washington Hospital Center, 110 Irving Street, N.W., Washington DC, 20010 USA. Current address: Department of Anaesthesia, Green Lane Hospital, Auckland, New Zealand. Accepted 18 July 1990. 0003-2409/91/100828 +05 $03.00
@ 1991 The Association of Anaesthetists of Gt Britain and Ireland
828
829
Comparison of azapropazone and aspirin induced with thiopentone 5 mg/kg and neuromuscular blockade obtained with vecuronium 0.1 mg/kg. Nasotracheal intubation was performed and a throat pack inserted. Anaesthesia was maintained with nitrous oxide and enflurane in oxygen, supplemented by fentanyl 1 pg/kg every 30 minutes. The patients’ lungs were ventilated mechanically. Residual neuromuscular blockade was antagonised with neostigmine 2.5 mg plus glycopyrronium 0.5 mg. Electrocardiogram and arterial pressure were monitored noninvasively throughout the procedure. At the conclusion of surgery patients were transferred to the recovery room where they were questioned at 15 minute intervals about their pain. Treatment of any pain was provided in one of three groups A, B or C as outlined below. The study drug was administered by mouth on a doubleblind and randomised basis when the patient first complained of pain in the postoperative period, provided that this occurred within the first 4 postoperative hours. Group A received aspirin 600 mg, group B azapropazone 300 mg, and group C azapropazone 600 mg. Morphine 10 mg was given intramuscularly as a rescue analgesic if adequate pain relief was not obtained within 90 minutes of administration of the drug. If supplementary analgesia was required because of the return of pain after initially adequate analgesia, paracetamol 1 g was given by mouth. Pain was assessed using a 10 cm visual analogue scale (VAS) and by a four-point ordered-category scale as follows; 0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain. The degree of postoperative trismus was assessed by determining the extent of mouth opening (measured as the distance between upper and lower incisors on full opening of the mouth, using metal calipers) and noting any changes in measurements postoperatively. Assessments were carried out at the time of first request for analgesia time 0, and at 0.5, 1, 2, 4, 6 and 8 hours thereafter, and finally on the morning of the following day. Mouth opening was assessed before operation in addition to the above times. Patients who were withdrawn from the study were recorded as such, together with the reason for their withdrawal. The need for additional analgesia was noted, as was any evidence of postoperative haemorrhage and the occurrence of any other side effects. Venous blood samples (10 ml) were taken for azapropazone assay from 17 patients in group B and 20 in group C at 30 minutes and at 1, 2, 4, 6 and 8 hours. Azapropazone concentrations were analysed using a modification of that method described by Farrier.24 This analysis was used to avoid interference by paracetamol. The method is linear to above 100 pg/ml. The coefficient of variance was at 10 pg/ml 4.9%, and at 50 pg/rnl 3.8%. Recoveries were better than 95%. Statistical significance for any differences between treatments was taken as p < 0.05. Data were assessed for suitability for parametric analysis of variance (ANOVAR). Sex, use of rescue and supplementary analgesia, numbers of withdrawals and incidence of side effects were assessed by Chi-squared tests. Mouth opening and VAS pain scores were assessed by one-way analysis of variance at each time of measurement, and further compared by covariant analysis; the covariate was the pre-induction and baseline (T = 0) values for mouth opening, and the baseline values for VAS. Category pain scores were assessed initially by
Table 1. General patient description, mean (SD) Ages; years Group A (n = 29) Group B (n = 24) Group C (n = 28)
24.4 23.2 26.0
(5.7) (5.4)
(7.1)
Weight; kg Group A (n = 29) Group B (n = 25) Group C (n = 26)
(10.1)
63.9 59.6 65.1
(10.1) (11.4)
Females
Males ~~
Group A Group B Group C
20 19 22
8 5 6
Chi-squared tests at each time point, and subsequently changes from the baseline value were analysed in a similar manner. Where treatment differences were indicated by the analysis of variance and covariance, these were tested further using Duncan’s multiple range test. Results
Six patients did not require analgesia during the first 4 hours after operation and therefore did not contribute to the results of the study. Of the remaining 80 patients, 28 received aspirin 600 mg (group A), 24 azapropazone 300 mg (group B) and 28 azapropazone 600 mg (group C). There were no significant differences between the groups with regard to age, sex and weight distribution (Table I), initial baseline pain score, and extent of surgery. The mean time of study drug administration was 30.5 minutes after awakening. Thirty-seven percent of patients who requested analgesia did so immediately on awakening; 70% of patients had received study medication within the first postoperative hour and 97% within 90 minutes. Analysis of variance for pain scores (Fig. 1) indicated significant treatment differences at one hour after administration only; group B had a significantly lower mean score than group C. Group A was intermediate between the other groups and did not differ significantly from either. Analysis of covariance indicated significant effects of the initial (T = 0) value at 0.5, 1, 2 and 8 hours only and significant treatment differences at one hour only; group B had a significantly lower mean score than groups A or C. 60 r 50
ld n 1
4 Time (hours)
6
0
Fig. 1. Visual analogue scale (mm) after the operation
2
4
(m, aspirin;
B, azapropazone 300 mg; 0 , azapropazone 600 mg).
M . A . Garrioch, G . J. Wardall and W. Fitch
830
Table 2. Pain score frequencies. ~~
Time
Score
0 hours
Group A Group B Group C
GroupA Group B GroupC GroupA Group B Group C GroupA Group B Group C
0.5 hours
1 hour
2 hours
4 hours
Group A Group B GroupC GroupA
6 hours
Group B
Group C GroupA Group B Group C Group A Group B GroupC
8 hours
24 hours
0 0
Chi-squared
d.f.
P
4.826
4
ns
1 0
1 2 3 11 12 5 5 8 9 5 13 9
0 1 1
10 7 5
12 6 11 5 14 7
1.347
4
ns
2 3 0
12 9 3 9 8 0 10 13 3
6.963
6
ns
3 4 2
16 12 13
5 2 6
1 1 1
2.280
4
ns
8 7 3
11 5 16
5 0 5 1 2 0
9.685
4
< 0.05
11
7 7 13
4 0 3 0 0 0
6.387
4
ns
7 8 8 7 6
13 6 9
0 0 1 0 2 0
0.766
2
ns
14 10 17
7 7 3
0 0 0 0 0 0
3.296
2
ns
Table 3. Use of rescue analgesia (intramuscular morphine).
Group
Number of patients needing rescue
Time of rescue; minutes, mean (SD) range
A
9 10 11
59 (41) 20-150 53 (33) 15-125 74 (40) 32-180
B C
Assessment of the ordered category pain scores (Table 2 ) at each time point indicated significant differences at 4 hours only; these differences were largely because of the increased frequency of patients scoring one in group C compared to other groups. Analysis of change from the zero time score showed no significant differences between the three groups at any time. 40
-
35
E
-Em 30 5 c a W
5 25
9 20
Before operation
0
0.5
I
2 4 Time (hours)
6
8
Fig. 2. Mouth opening (mm) before and after the operation (m, aspirin; B, azapropazone 300 mg; azapropazone 600 mg).
n,
n 8 10
11
ANOVAR for mouth opening data (Fig. 2 ) indicated significant treatment differences at one and two hours after drug administration; group C had significantly lower mean mouth opening than A or B. Analysis for covariance indicated significant effects of the TO value at all times following drug administration, but no effect on the preinduction value. Analysis of covariance was thus repeated using only the baseline TO value as covariate and this analysis indicated significant differences at T1 only; again group C had a significantly lower mean mouth opening than A or B. Supplementary analgesia with paracetamol 1 g was provided for 18 patients (64%) in group A, 14 (58%) in group B and 15 (53%) in group C. There were no significant differences between groups. Rescue analgesia was needed for 30 patients (Table 3). There were no significant differences between groups either in numbers of patients requiring such analgesia or in the times at which it was administered. Nineteen patients were withdrawn from the study (Table 4). Of these, 13 withdrawals had inadequate pain relief, even after intramuscular morphine, and six had difficulties with blood sampling or were uncooperative. No significant differences were found between the number withdrawn in each group. Table 5 gives side effects as volunteered by patients.
Comparison of azapropazone and aspirin
831
Table 4. Patients withdrawn from the study. Group
A B C
Number withdrawn Remaining Chi-squared d.f. p 5 7
0.95
23 17 21
7
2
ns C
Withdrawn for 'inadequate pain relief (n) A B C
0
z 30t
0
3 5 5
There were no significant differences between groups. Mean plasma azapropazone levels are shown in Fig. 3 .
3
2
4
5
I
I
I
6
7
8 0
Time (hours)
Plasma azapropazone concentrations (pgiml) after administration of azapropazone 300 mg and azapropazone 600 mg ( 0 ,azapropazone 300 mg; *, azapropazone 600 mg).
Fig. 3.
Discussion Several previous s t ~ d i e s l ,attest ~ . ~ to the efficacy of orally administered nonsteroidal anti-inflammatory drugs in relieving the pain associated with oral surgery. It is therefore surprising that the main finding of the present study was the disappointing quality of analgesia obtained in all treatment groups. Approximately one third of the patients required the administration of a rescue opioid and a further number were withdrawn when analgesia was considered inadequate, despite the administration of 10 mg morphine. Theoretically, this situation must have arisen because the pain associated with oral surgery was much more severe than anticipated thus it should have been treated with potent analgesics ab initio; the drugs employed in the investigation did not possess adequate analgesic properties; the time of drug administration was inappropriate or a combination of all of these. There is no doubt that the pain experienced by the patient, as indicated by the high initial visual analogue scores, was severe before they requested an analgesic. The day-to-day practice of anaesthesia demonstrates clearly that the control of pain is much easier if an analgesic is administered before the pain becomes severe." Pain is a subjective phenomenon; nevertheless, the relatively unsatisfactory nature of the analgesia obtained in this study may have been due, in part at least, to the stoical nature of the patients; the request for analgesia only occurred once the pain had already become intense. In this context, it may be relevant to note that most of the previous studies on the analgesic efficacy of NSAIDs were carried out in North America and it is conceivable that earlier requests for pain relief yielded more satisfactory results. Another factor which may be considered is that previous studies were carried out by nonanaesthetists, notably clinical pharmacologists and oral surgeons. It may be that these investigators have a different perception as to what constitutes satisfactory postoperative analgesia. They may also be less willing to administer potent opioid analgesics because of concern about side effects.
The drugs used in the study do undoubtedly possess analgesic properties. Aspirin has been used extensively in the treatment of mild to moderate pain.5,R-'0.'4 Azapropazone has been used for some time for the treatment of rheumatic conditions and a large number of studies attest to its analgesic efficacy for this purpose.18-20 However, certain questions remain unanswered. We are at a loss to explain why no difference in plasma levels of azapropazone 300 mg and 600 mg doses was shown. In fact all previous work investigating azapropazone has assessed the drug by analgesic activity i.e., ability to modify pain threshold, not by measurement of plasma levels.23Thus we believe our work to be the first to compare plasma level with analgesic effect. Work previously done in healthy human volunteer^'^ indicates that peak plasma levels of azapropazone occur about 90 minutes after administration, thus we were disappointed to find that this did not occur in our study. The timing and method of drug administration was also shown to be inappropriate because postoperative plasma drug concentrations were so low they gave minimal analgesia. It should also be noted that a high degree of variability exists in these postoperative plasma concentrations; some patients had only traces of azapropazone in the blood up to 4 hours after administration, whereas in a small minority concentrations were surprisingly high. There are several possible explanations for this. Gastric emptying may well have been markedly reduced because of the pain experienced by some patients. Another theory is that the administration of opioids during the operation inhibited the entry of drug into the duodenum thus slowing absorption, although recent workz2 suggests that fentanyl may not have this effect. In retrospect, it would have been useful to measure the postoperative concentrations of aspirin to reinforce these findings, but unfortunately this was not done. Previous studies of a similar nature did not include measurement of
Table 5. Side effects. ~
Group A B C
_____
~~
None
Nausea
Headache
Sore throat
Bleeding
Other
18 19 18
4
1
2
3 3
1 2
1
2 0 2
1 0
0
1
832
M . A . Garrioch. G . J. Wardall and W . Fitch
plasma drug concentrations a n d thus cannot aid our conclusions. In conclusion, this study, in contrast to previous work, shows that NSAIDs given orally are not an efficacious means of providing analgesia in a large number of patients following dental extractions. We believe that the subject warrants further study by anaesthetists, since they are often involved in the initial prescription of postoperative analgesia for such patients. Our findings do highlight the importance of achieving, a n d verifying, therapeutic concentrations of such drugs (particularly after oral administration) before drawing conclusions on analgesic efficacy.
References 1. COOPERSA. Five studies on ibuprofen for postsurgical dental
pain. The American Journal of Medicine 1984; 11: 70-7. RJ, MONCADA S, VANEJR. Analgesic, antipyretic and 2. FLOWER anti-inflammatory agents; drugs employed in the treatment of AG, GOODMAN LS, RALLTW, MIVADF, gout. In: GILMAN eds. The pharmacological basis of therapeutics. New York: Macmillan, 1985: 674-715. 3. SEYMOUR RA. Use of analgesics in postoperative dental pain; a review. Journal of the Royal Society of Medicine 1984; 17: 949-54. SH. Peripheral analgesia; mechanism of the 4. FERREIRA analgesic action of aspirin like drugs and opiate-antagonists. British Journal of Clinical Pharmacology 1980; 1 0 237s-45s. 5. HIGGS GA. Arachidonic acid metabolism, pain and hyperanalgesia; the mode of action of non-steroid mild analgesics. British Journal of Clinical Pharmacology 1980; 10: 233s-5s. 6. NICKARDERR. Non-steroidal anti-inflammatory agents. Annual Review of Pharmacology and Toxicology 1979; 1 9 469-90. 7. REYNOLDS JEF, ed. Martindale-the extra pharmacopoeia. London: Pharmaceutical Press, 1989: 9. HT, LASAGNA L, GILLIES 8. CALIMLIM JF, WARDELL WM, DAVIS AJ. Analgesic efficacy of an orally administered combination of pentazocine and aspirin. Clinical Pharmacology and Therapeutics 1977; 21: 34-43. JA, WHITE RW, WHITE EH, HUGHESMK. An 9. FORBES evaluation of the analgesic efficacy of proquazone and aspirin in post-operative dental pain. Journal of Clinical Pharmacology 1980; 2 0 465-74.
10. OKUN R, GREEN JW, SHACKELFORD RW. An analgesic comparison study of indoprofen verses aspirin and placebo in surgical pain. Journal of Clinical Pharmacology 1979; 19 487-92. 11. SCOTTR, ELLISE, UPTONLG. Double-blind evaluation of etodolac (200 mg, 400 mg) compared with zomepirac (100 mg) and placebo on third molar extraction pain. Oral Surgery, Oral Medicine and Oral Pathology 1986; 6 2 63842. 12. MEHLISCHDR, JOY ED. Zomepirac sodium vs APC with codeine for oral surgery pain. Journal of Oral Surgery 1981; 3 9 426-9. JK. Diflusinal, a new analgesic, in the treatment of 13. PETERSEN postoperative pain following removal of impact mandibular third molars. International Journal of Oral Surgery 1979; 8 102-1 3. 14. COOPERSA. Comparative analgesic efficacies of aspirin and acetaminophen. Archives of Internal Medicine 1981; 141: 282-5. 15. LEACHH. The determination of azapropazone in blood plasma. Current Medical Research and Opinion 1976; 4: 3543. 16. GILLIESGWA, KENNYGNC, BULLINGHAM RES, MCARDLE CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral, non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 4 2 727-31. JMG, WEDLEYJR, ADAMS 17. JONESRM, CASHMAN JN, FOSTER AP. Comparison of infusions of morphine and lysine acetyl salicylate for the relief of pain following thoracic surgery. British Journal of Anaesthesia 1985; 57: 259-63. 18. HINGORANIK . A comparative study of azapropazone and ibuprofen in the treatment of osteoarthrosis of the knee. Current Medical Research and Opinion 1976; 4:57-64. AJM, MOLLJMH, HORTJF. A comparison of three 19. FRANK ways of measuring pain. Rheumatology and Rehabilitation 1982; 21: 211-7. 20. KEANWF, KRAAGGR, ROONEYPJ, CAPELLHA. Clinical therapeutic trial of aspirin and azapropazone in rheumatoid arthritis when prescribed singly and in combination. Current Medical Research and Opinion 1981; I: 164. or relief! 21. ARMITAGEEN, Postoperative pain-prevention British Journal of Anaesthesia 1989; 63: 136-8. K, ANDREASEN F, 22. SCHURIZEK BA, WILLACYLA, KRAGLUND JUHL B. Antroduodenal motility, pH and gastric emptying during balanced anaesthesia; comparison of pethidine and fentanyl. British Journal of Anaesthesia 1989; 6 674-82. 23. GABKA J. The dose dependent analgesic effect of intravenously administered azapropazone. Clinical Trials Journal 1983; 2 0 219-230. DS. Re: Analysis of azapropazone. Arzneim-Forsch. 24. FARRIER 1974: 24: 747.
