Long-Acting Analgesic Or Long-Acting Local Anesthetic in Controlling Immediate Postoperative Pain After Lower Third Molar Surgery

SCIENTIFIC ARTICLES

Long-Acting Analgesic or Long-Acting Local Anesthetic in Controlling Immediate Postoperative Pain After Lower Third Molar Surgery

J.B. Rosenquist1'2 and E. Nystrom2 'Department of Oral Surgery, University of Umea, Sweden and 2Department of Oral Surgery and Oral Medicine, University of Hong Kong, Hong Kong

Summary In a double-blind crossover study, the effect on postoperative pain of lidocaine plus diflunisal was compared with that of bupivacaine and placebo. Forty-eight patients with bilateral impactions of lower third molars had these removed on two occasions four weeks apart. One pain-control regimen was used on one occasion and the alternate on the second. The pain intensity was indicated on a visual analog scale at 2, 3, 4, 5, and 6 hours postoperatively. The pain values for the first postoperative hours were higher for the lidocaine diflunisal combination, whereas after 5 hours the opposite was true. Significantly more patients preferred the combination of lidocaine and diflunisal. Three patients reported fatigue postoperatively during the day of surgery, which they attributed to the operation and not to the analgesics used.

One of the most commonly encountered discom- hours compared to 2 hours for aspirin.13 The long- forts after oral surgery procedures, particularly lower lasting action of diflunisal carries over the first 6-8 third molar surgery, is pain. The surgical trauma postoperative hours during which the postoperative elicits a variety of tissue responses producing and pain after third molar surgery reaches its peak.14 releasing biochemical mediators involved in the pain Preoperative intake of analgesics would allow for a process. Among these are the prostaglandins, de- reasonable serum level to be achieved once the ef- rivatives of arachidonic acid.' 2 They play a part in fect of the local anesthetic is wearing off, thus limit- inducing the inflammatory response3'4 and are also ing the release and synthesis of the substances in- known to lower the nociceptor threshold5 and sen- volved in the pain process. In this context, sitize the nociceptors to stimulating substances such acetaminophen15 has not offered any advantage, as bradykinin and histamine,6 which are also re- which might be explained by its greater central nerv- leased by the tissue damage. The synthesis of ous system activity compared to that in the prostaglandins is suppressed by a number of anti- periphery.13 However, more peripherally active sub- inflammatory agents7-9 including the nonsteroidal stances such as ibuprofen16 and flurbiprofen17 have anti-inflammatory drugs (NSAIDs). been shown to be effective when given preopera- Diflunisal, a salicylic acid derivative, is a NSAID tively. Although no subsequent studies have been which offers advantages over the more commonly carried out to support the finding, the claim that diflun- used aspirin, particularly in that it has a longer isal when given preoperatively increases the inci- duration10 and is less irritating to the gastric mu- dence of alveolitis18 has discouraged its use cosa.11 Its absorption is only slightly affected by the preoperatively. content of the stomach12 but it requires a longer An alternative to analgesics in controlling post- period to reach its peak plasma concentration, 2-3 operative pain is the use of long-acting local anesthetics such as bupivacaine. At a concentration of 5 mg/ml, bupivacaine is equipotent to the commonly used lidocaine concentration of 20 mg/ml,19 but its Received August 6, 1986; accepted December 29, 1986. duration is two to three times longer.20 This should Address correspondence to Professor J.B. Rosenquist, De- increase the pain-free interval postoperatively and partment of Oral Surgery and Oral Medicine, 2/F, The Prince Philip consequently lessen the need for postoperative Dental Hospital, Hospital Road, Hong Kong. analgesics.

6 ANESTHESIA PROGRESS This study was undertaken with the objective of Results comparing the effect on postoperative pain of the combination of a relatively short-acting local anesthetic and a long-acting analgesic (lidocaine plus difluni- Of the 48 patients originally included in the study, sal) with that of a long-acting local anesthetic one was excluded as the questionnaire was not re- (bupivacaine plus placebo). This was done using a turned. Remaining were 47 patients, 24 men and 23 double-blind crossover design and the bilaterally im- women with a mean age of 24.1 years (range 18-37 pacted lower third molar model. years). The amounts of local anesthetic used were Methods 2.8±0.2 ml for the LID procedure and 2.8+0.4 ml for the B/PL procedure. The duration of surgery (start of injection-end of Patients on the waiting list for removal of impacted operation) was 26.2+±9.2 min for the L/D procedure lower third molars at the Department of Oral Surgery, and 30.2±9.4 min for the B/PL procedure. In 8 pa- University of Umea, were screened for this study. tients the difference in operation time between the Forty-eight of those, who had bilateral impactions of two procedures was more than 10 minutes, 4 cases similar difficulty and were of ASA physical status I due to difficulties in obtaining good anesthesia and category, were included. Patients with a drug history in 4 cases due to a slightly more complicated opera- other than oral contraceptives and pregnant women tion. Four of them were among 6 patients not indicat- were excluded. ing their preference for any pain control regimen and The study was designed as a double blind cross- of the remaining four, two preferred the regimen used over study. The impacted teeth were removed in two for the longer operation and two that of the shorter sessions four weeks apart. In one session lidocaine one. (20 mg/ml) with epinephrine (12.5 ug/ml) was used After the B/PL procedure 3 patients took rescue as local anesthetic and in the other session analgesics during the first 6 postoperative hours and bupivacaine (5 4g/ml) with epinephrine (5 ,ug/ml) 23 thereafter, most of them (15) between 7 and 9 was used. The other of the procedures was ran- hours postoperatively. Four of the patients taking domized as was the side of the extractions. rescue analgesics after the B/PL procedure also took When the patients had lidocaine (L) as the local rescue analgesics with the L/D procedure, one during anesthetic, they were given two 250 mg diflunisal (D) the first 6 postoperative hours and 3 thereafter. No tablets to be taken two hours after the injection patient took any rescue analgesics only after the LID (Group L/D), whereas those who had bupivacaine (B) procedure. as the local anesthetic, were given two placebo (PL) Twenty-nine patients preferred the LID regimen tablets with the same instructions (Group B/PL). Dif- and 12 the MIPL regimen, whereas 6 patients had not lunisal tablets (10 x 250 mg) were supplied as rescue answered the question about preference (Fig. 1). The analgesics. The patients were asked to wait as long as possible before taking any rescue analgesic and indicate, when taken, the pain intensity on a visual Number analogue scale (see below). of patients Two hours after the start of operation, viz, when analgesic or placebo was taken, the patients indicated the level of pain on a horizontal visual analogue scale, 100 mm long, with the endpoints defined as "no pain and "very severe pain." This was repeated 29 at three, four, five, and six hours postoperatively. Sutures were removed one week postoperatively. The patients were also asked to comment on their experience of the postoperative period including comments on side effects attributable to the drugs used. At the time of suture removal after the second operation, they were asked abouttheir preference for 12 pain control regimen. The investigation was approved by the Ethical Committee ofthe University Hospital, Umea, and oral consent was obtained from all patients. I IF s sE ss Chi-square test was used for statistical analyses of - 6omm-L patients' preference and sign test for the analysis of Fig. 1 - Patients' preference of pain control regimen. Significantly difference in VAS values at each observation time. more patients prefer lidocaine plus diflunisal than Student's t-test was employed for analysis of VAS bupivacaine plus placebo (p < 0.05). C1 Lidocaine plus values from the parallel groups. diflunisal; Z2 bupivacaine plus placebo; liD no reply.

JANUARY/FEBRUARY 1987 7 difference between the two pain control regimens TABLE 1 Number of Patients with Higher VAS Values After was statistically significant (p < 0.05). One Pain Control Regimen Than After the Other. When Pain is Sixteen patients commented that the long-acting Assessed at 2, 3, 4, 5, and 6 Hours Postoperatively (Patients anesthesia (B/PL) was unpleasant. Out of four pa- Taking Analgesics Not Excluded) tients with similar and very low (less than 5) VAS Higher VAS PotoperatIon hours values throughout the first 6 hours after both opera- tions, two preferred the L/D regimen. Three patients values after 2 3 4 5 6 commented that a long-acting local anesthetic was good. Lidocaine + diflunisal 25b 33a 20 16 8b The mean VAS values at each postoperative hour No difference 13 7 3 4 3 were significantly different between the two Qpera- Bupivacaine-placebo 9 7 21 27 35 tions at 2, 3, 5, and 6 hours (Fig. 2). When the VAS Missing data 0 0 3 0 1 values were compared intraindividually more pa- ap <0.01. tients had higher values with the LID regimen than bp < 0.001. with the B/PL regimen at two hours (p < 0.01) and at Probability estimated by sign test. three hours (p < 0.001) whereas at six hours, the opposite was true (Table 1). None of the patients reported any side effects which they attributed to the drugs. However, 4 pa- Discussion tients experienced discomfort other than postopera- The present investigation was carried out as a tive pain and swelling. Two were tired on the day of double-blind crossover study, which allowed for an surgery after the B/PL procedure and one after the evaluation of patients' preference. A two-hour inter- L/D procedure, all of them attributing this to the val between start of operation and intake of surgery. A fourth patient had a cold, which started at analgesics/placebo was chosen as this would allow the eve of the day of surgery after the L/D procedure administration while the local anesthetic was still in and continued for another 3 days. In no case was the effect but before analgesics were needed for pain postoperative course complicated by alveolitis. relief.21 In the questionnaire, patients were asked to list pain score side effects and which of these they attributed to the (VAS - values) drugs used. In most studies patients are not asked to Am,tu0 r make such a distinction. Consequently, side effects are often reported as drug effects. Had this approach been used, the reported incidence of side effects would still have been low indicating that diflunisal is a well tolerated drug. In studies comparing different kinds of local anesthetics in which no analgesics or placebo were subject to study, no side effects were 20 I mentioned-O or observed."3 A low incidence of alveolitis after third molar surgery is the experience of this clinic.15 Obviously, the alleged effect of diflunisal when given preoperatively"8does not occur when the drug is given postoperatively. It has been shown earlier that a single dose of 500 mg of diflunisal has a duration of effect of about 8 10 hours and significantly reduces pain after third molar surgery for at least four hours after intake with an observed effect exhibited within one hour (paper submitted for publication). It also seems as if the analgesic efficacy is more pronounced in patients taking analgesic at low pain intensities.21 In the present study, diflunisal needed 2-3 hours before its effect was reflected in decreased in- i I I I pain 2 3 tensity. However, there was an obvious long-term 4 5 6 hours effect posoeravl yielding lower pain intensity values at six hours with the LID regimen as compared to the values with Fig. 2 - Pain intensity scores (VAS values) during the first 6 the B/PL regimen. The duration of effect was prob- postoperative hours for lidocaine plus diflunisal ably longer as very few (x---- x) and bupivacaine plus placebo (o-o). There patients needed additional are statistically significant differences at 2 (p < 0.01), 3, analgesics with the LID regimen. This is in agreement 5, and 6 hours (p < 0.001) as analyzed with Students with the study by Honig23 on postoperative pain after t-test. meniscectomy.

8 ANESTHESIA PROGRESS With the long duration of bupivacaine it was antici- 6. Vane JR: Prostaglandins as mediators of inflammation. Adv pated that the use of this alone would give the pa- Prostaglandin Thromboxane Res 2:797-801, 1976. 7. Ferreira SH: Prostaglandins, aspirin-like drugs and analgesia. tients as long a pain relief as the combination of Nature New Biol 240:200-203, 1972. lidocaine and diflunisal, but this proved not to be so. 8. Ferreira, SH, Moncada S, Vane JR: Indomethacin and aspirin Although the mean pain intensity did not differ be- abolish prostaglandin release from the spleen. Nature New tween the two procedures, the relatively short dura- Biol 231:237-239, 1971. 9. Vane JR: Inhibition of prostaglandin biosynthesis as the tion of action of bupivacaine could explain why pa- mechanism of action of aspirin-like drugs. Nature New Biol tients expressed preference for the combination of 231:232-235, 1971. lidocaine and diflunisal. Had a bupivacaine solution 10. Forbes JA, Calderazzo JP, Bowser MW, Foor VM, of 7.5 mg/ml been used resulting in a longer duration Schackleford RW, Beaver WT: A 12-hour evaluation of the of anesthesia, it could be argued that the preference analgesic efficacy of diflunisal, aspirin and placebo in postoperative dental pain. J Clin Pharmacol 22:89-96, 1982. might have been different. However, 45% of the pa- 11. Caruso J, Fumagalli M, Montrone F, Vemazza M, Bianchi tients (21 out of 47) did not require any rescue Porro G, Petrillo M: Controlled, double-blind study comparing analgesic with the B/PL regimen, which is a higher acetylsalicylic acid and diflunisal in the treatment of osteoar- percentage than reported by Danielson et al.22 using thritis ofthe hip and/or knee; long-term gastroscopic study. In: a in Miehlke K, ed., Diflunisal in Clinical Practice, New York, Fut- higher (7.5 mg/ml) concentration of bupivacaine ura Publishing Co., Inc., 1978. the local anaesthetic. This might indicate that the 12. Tempero KF, Steciman SL, Besseloor GH, Smit-Sibinga C higher concentration is not more effective in alleviat- TH, de Schepper P, Tjandramaga TB, Dresse A, Gribnau ing pain even if it prolongs the period of anesthesia. FWJ. Special studies on diflunisal, a novel salicylate. Clin Res Moreover, in the present study, the majority of the 23:224A, 1975. 13. Flower RJ, Moncada S, Vane JR: Analgesic-antipyretics and patients preferring the L/D regimen found long-acting anti-inflammatory agents; drugs employed in the treatment of anesthesia unpleasant. It is therefore not very likely gout. In: Goodman-Gilman A, Goodman LS, Rail TW, and that a further extended period of anesthesia would Murad F, eds., The Pharmacological Basis of Therapeutics, have been met with more enthusiasm. 7th ed, New York, Macmillan, pp. 674-715, 1985. Based on the results of this study, the combination 14. Szmyd L, Shannon IL, Mohnac AM: Control of postoperative sequelae in impacted third molar surgery. J Oral Therap of a relatively short-acting local anesthetic and a Pharmacol 1:491-496, 1965. long-acting analgesic as a postoperative pain control 15. Gustafsson I, Nystrom E, Quiding H: Effect of preoperative regimen seems superior to the use of a long-acting paracetamol on pain after oral surgery. Eur J Clin Pharmacol local anesthetic alone. Whether it is preferred to a 24:63-65, 1983. combination 16. Dionne RA, Campbell RA, Cooper SA, Hall DL, Burkingham of long-acting anesthetic and long- B: Suppression of postoperative pain by preoperative admin- acting analgesic, which the comments of the patients istration of ibuprofen in comparison to placebo, seem to indicate, is the aim of a study presently in acetaminophen and acetaminophen plus codeine. J Clin progress. Pharmacol 23:37-43, 1983. 17. Dionne RA: Suppression of dental pain by the preoperative administration of flurbiprofen. Am J Med 80 (Suppl 3A): 41-49, 1986. References 18. Petersen JK: The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars. Curr Med Res Op 5:525-535, 1978. 1. Bergstrom S, Danielsson H, Samuelsson B: The enzymatic 19. Covino BG and Vassallo HG: Localanesthetics. Mechanisms formation of prostaglandin E2 from arachidonic acid. Biochim of Action and Clinical Use. New York, Grune and Stratton, Biophys Acta 90:207-210, 1964. Inc., 1976. 2. Van Dorp DA, Beerthuis RK, Nugteren DH, von Keman H: The 20. Chapman PJ and Macleod AWG: A clinical study of biosynthesis of prostaglandins. Biochim Biophys Acta bupivacaine for mandibular anesthesia in oral surgery. 90:204-207, 1964. Anesth Prog 32:69-72, 1985. 3. Graeves MW, Sondergaard J, McDonald-Gibson W: Recov- 21. Quiding H, Oksala E, Happonen RP, Lehtimaki K, Ojala T: The ery of prostaglandins in human cutaneous inflammation. Br visual analogue scale in multiple-dose evaluations of Med J: 2:258-260, 1971. analgesics. J Clin Pharmacol 21:424-429, 1981. 4. Kaley G and Weiner R: Prostaglandin E - a potential mediator 22. Danielsson KH, Evers H, Holmiund A, Kjellman 0, Nordenram ofthe inflammatory response. Ann NY Acad Sci 180:330-350, A, Persson SE: Long-acting local anaesthetics in oral surgery. 1971. Clinical evaluation of bupivacaine and etidocaine for mandibu- 5. Perl ER: Sensitization of nociceptors and its relation to sensa- lar nerve block. Int J Maxillofac Surg 15:119-126, 1986. tion. In: Bonica JJ and Able-Fessard DG, eds., Advances in 23. Honig WJ: Clinical comparison of the analgesic efficacy of Pain Research-Therapy, vol. 1, New York, Raven Press, pp. suprofen, diflunisal and placebo in the treatment of pain after 17-34, 1976. meniscectomy. Pharmacology 27 (suppl 1):74-80, 1983.

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