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    Efficacy and safety of combined Efficacy and safety of combined Document Transcript

    • Brazilian Journal of Medical and Biological Research (2006) 39: 1241-1247 1241Efficacy and safety of combined piroxicam treatmentISSN 0100-879X Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery A.B. Barroso, V. Lima, Unidade de Farmacologia Clínica, Departamento de Fisiologia e Farmacologia, G.C. Guzzo, R.A. Moraes, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil M.C. Vasconcellos, M.M. Bezerra, F.A.L. Viana, R.C.R. Bezerra, G.S.M. Santana, F.A. Frota-Bezerra, M.O. Moraes and M.E.A. Moraes AbstractCorrespondence Third molar extraction is a common procedure frequently accompa- Key wordsM.E.A. Moraes nied by moderate or severe pain, and involves sufficient numbers of • PiroxicamRua Cel. Nunes de Melo, 1127 patients to make studies relatively easy to perform. The aim of the • Dexamethasone60420-270 Fortaleza, CE present study was to determine the efficacy and safety of the therapeu- • OrphenadrineBrasil • CyanocobalaminFax: +55-85-3223-2903 tic combination of 10 mg piroxicam, 1 mg dexamethasone, 35 mg • PainE-mail: betemora@ufc.br orphenadrine citrate, and 2.5 mg cyanocobalamin (Rheumazin®) when • Mandibular molar surgery compared with 20 mg piroxicam alone (Feldene®) in mandibular thirdResearch supported by CNPq and molar surgery. Eighty patients scheduled for removal of the thirdby Instituto Claude Bernard-InCB, molar were included in this randomized and double-blind study. TheyBrazil. received (vo) Rheumazin or Feldene 30 min after tooth extraction and once daily for 4 consecutive days. Pain was determined by a visual analogue scale and by the need for escape analgesia (paracetamol).Received November 29, 2005 Facial swelling was evaluated with a measuring tape and adverseAccepted July 17, 2006 effects and patient satisfaction were recorded. There was no statisti- cally significant difference in facial swelling between Rheumazin and Feldene (control group). Both drugs were equally effective in the control of pain, with Rheumazin displaying less adverse effects than Feldene. Therefore, Rheumazin appears to provide a better risk/ benefit ratio in the mandibular molar surgery. Since the side effects resulting from nonsteroidal anti-inflammatory drug administration are a severe limitation to the routine use of these drugs in clinical practice, our results suggest that Rheumazin can be a good choice for third molar removal treatment. Introduction molar extraction is a common procedure ac- companied frequently by pain of moderate Pain after third molar extraction has be- or severe intensity, and involves sufficient come the model most frequently used in numbers of patients to make studies rela- acute pain trials. The reason is that third tively easy to perform (1). The pain and Braz J Med Biol Res 39(9) 2006
    • 1242 B.A. Barroso et al. swelling resulting from the surgery are gen- mg dexamethasone, 35 mg orphenadrine ci- erally caused by different factors, such as trate, and 2.5 mg cyanocobalamin (Rheu- surgical trauma or endotoxins, which are mazin®) in comparison to 20 mg piroxicam treated with various therapeutic agents, in- (Feldene®) alone in a mandibular third mo- cluding nonsteroidal anti-inflammatory drugs lar surgery, evaluating pain and swelling. (NSAIDs, e.g., piroxicam, diclofenac, cele- coxib), antibiotics, and others (2). Material and Methods Various doses of piroxicam (5 to 40 mg) have been tested for postoperative dental Patients pain. Although neither 5 nor 10 mg piroxicam produced clinically significant analgesia, Eighty healthy adults, 25 men and 55 higher doses were significantly superior to women requiring removal of mandibular third placebo, and both the 20- and 40-mg doses molars, participated in the study. All pa- were comparable to 648 mg aspirin during tients had their healthy condition confirmed the initial 6 h. Piroxicam at 20 and 40 mg by clinical and laboratory examinations. They produced a significantly longer duration of had not taken any medication in the previous analgesia than did 648 mg aspirin, and the 3 months that might affect inflammatory analgesic effect of piroxicam appears to last responses, had no systemic diseases, did not for up to 24 h in a substantial number of consume alcohol, did not smoke, nor did patients (3). However, 20 or 40 mg piroxicam they have any other condition that might induces the typical side effects of this drug interfere with the results. In addition to these class such as gastroduodenal hemorrhagic systemic parameters, the position of the tooth, episodes or renal function damage. as described in the study design, was also The combination of piroxicam, dexameth- used as an inclusion criterion. The study was asone, orphenadrine citrate, and cyanoco- approved by the Ethics Committee of the balamin can reach several targets. Piroxicam Federal University of Ceará. The study was and dexamethasone can inhibit the activity conducted according to the 196/96 resolu- of cyclooxygenases and phospholipase A2, tion from the Brazilian Ministry of Health. respectively (4,5). These effects result in All participants were made aware of the reduced synthesis of prostaglandins and leu- possible risks and benefits of the study, and kotrienes, which are involved in the inflam- informed written consent was obtained from matory process. Orphenadrine citrate has them. The patients included in the study analgesic properties and is used as a muscle were aged 15 to 65 years, able to swallow relaxant in physical therapy to relieve pain tablets, and able to cooperate adequately and discomfort caused by strains, sprains, with the trial procedure. All women were and other muscle injuries (6). Vitamin B12, required to have a negative pregnancy test at also called cyanocobalamin, is an especially least 15 days before the surgery (9). important vitamin for maintaining healthy nerve cells, and contributes to the produc- Study design tion of DNA and RNA responsible for ge- netic expression (7). It may also improve A prospective, randomized, controlled, conditions for DNA synthesis, promoting a double-blind clinical trial was carried out to quick recovery of injured tissue after sur- determine the efficacy and adverse events of gery (8). the use of a combination of 10 mg piroxicam, The objective of the present study was to 1 mg dexamethasone, 35 mg orphenadrine determine the efficacy and safety of the thera- citrate, and 2.5 mg cyanocobalamin (Rheu- peutic combination of 10 mg piroxicam, 1 mazin®; Catafarma, Tubarão, SC, Brazil), orBraz J Med Biol Res 39(9) 2006
    • Efficacy and safety of combined piroxicam treatment 1243using single-agent 20 mg piroxicam (Fel- (basal data) and at the 6, 24, 48, 72, and 120dene®; Pfizer, São Paulo, SP, Brazil) as the h after treatment using a visual analoguepositive control. The surgeries, considered scale. This scale has 10 levels that representto be moderately difficult on the basis of the all pain sensations from none to maximum,tooth position, were carried out using stand- where 0 indicates no pain, 1-9 indicate in-ard procedures. A panoramic radiograph was creasing pain (mild to moderate intensity),obtained to determine the position of the and 10 corresponds to intolerable (severe)tooth. We chose patients who had erupted, pain. Pain scores were determined duringpartially erupted or impacted molars in com- the daily visits to the clinic (13). Patientsbination with any classical position accord- were asked to place a mark along the lineing to the Winter (10) or the Pell and Gre- that corresponded to the amount of pain theygory classification (11). Winter’s classifica- were experiencing (14).tion shows a relationship between the incli- During the study, patients were allowednation of the third molar and the distal sur- to take escape analgesia (750 mg paraceta-face of second molars (10), and the classifi- mol), if necessary, to relieve pain not con-cation of Pell and Gregory is widely used to trolled by the medications studied. The quan-predict the difficulty of extracting impacted tity of paracetamol was calculated in gramsmandibular third molars. The classification over the 5 days of study, with a maximumof such molars is based on their spatial rela- dose of 3 g of drug per day. The need fortionship (as shown by radiography) to the more than 6 g of escape analgesia in the firstascending ramus of the mandible and to the 48 h constituted failure to respond to treat-occlusal plane (11). Surgical time was esti- ment and the patient was excluded from themated to be less than 40 min. study. In all surgical dental extractions, 2% Immediately prior to anesthesia and sur-mepivacaine containing epinephrine (1: gery, all subjects were submitted to face100.000; 2% Scandicaine; Septodont, Saint- measurements using a calibrated metric scaleMaur-des-Fossés, Cedex, France) was used in millimeters, for later determination offor local anesthesia according to the tech- facial swelling. This was done by taking thenique of direct mandibular intraoral anesthe- sum of measures between three standardsia. Osteotomy with a 702 broach and simul- points demarcated with permanent ink. Thetaneous irrigation with physiological solu- first measurement was from the lower eartion were applied when necessary. lobe to the pogonion, passing through a third Each patient received one tablet of Rheu- point corresponding to the mandibular thirdmazin or Feldene orally 30 min after the molar on the outside part of the cheek (Fig-surgical procedure, and once daily for the ure 1, broken line, A). The second was fromfollowing 4 days. All medication was placed the lower ear lobe to the labial commissurein identical envelopes and clearly marked (Figure 1, solid line, B). The sum of thesewith the initials of each patient. Analgesic first measures was considered to correspondefficacy was determined according to post- to the basal data for each subject. Measure-operative pain using a visual analogue scale ments were then made at 6, 24, 48, 72, andand by the amount of paracetamol (750 mg) 120 h after surgery and compared to thetaken as escape analgesia (Tylenol; Janssen- respective basal data for each subject. AtCilag, São Paulo, SP, Brazil), whenever the each visit, patients receiving Feldene orpatient deemed it necessary, while the swell- Rheumazin were asked to report any dis-ing was assessed using a calibrated metric comfort during the study, besides adversescale as described later (12). effects. Pain scores were measured preoperatively At the end of the study (120 h), the Braz J Med Biol Res 39(9) 2006
    • 1244 B.A. Barroso et al. patients were asked to evaluate their treat- 50) years were included in the Rheumazin ment with regard to pain and swelling. The (R) group, and 41 patients with a mean age patients could classify their degree of satis- of 22.7 (16-43) years were included in the faction according to scores of 0, 1, 2, 3, or 4 Feldene (F) group. Both groups were con- as poor, moderate, good, very good, or ex- sidered to be homogenous for age and gen- cellent, respectively. der, with no statistically significant differ- ence between them (data not shown). Statistical analysis After surgery, significant differences were observed between the two groups. The maxi- Data were analyzed statistically by two- mum degree of pain was a score of 2, and the way repeated measures ANOVA to deter- prevalent scores were 0 or 1. Although there mine if there was a significant difference (P was no significant difference between the < 0.05), followed by a t-test, with α level two groups at other times, pain was signifi- adjusted by the number of time points (Bon- cantly lower (P < 0.05) in the Rheumazin ferroni correction). group compared to the Feldene group at the 6th and 120th hours (a score of 0 at 6 h (R = Results 25, F = 14) and at 120 h (R = 40, F = 33; Figure 2). This randomized controlled clinical trial Interestingly, considering the amount of enrolled 80 subjects undergoing surgical escape analgesia used, despite the lack of extraction of mandibular third molars. Thirty- statistical difference, the use of paracetamol nine patients with a mean age of 23.0 (15- was also lower for the test (Rheumazin) group (R = 0.15; 0.73-0.29), compared toFigure 1. Tape measuring Feldene (F = 0.23; 0.13-0.31). These datamethod for the evaluation of fa-cial swelling. The first measure- are reported as median and range of valuesment was from the lower ear lobe for escape analgesia.to the pogonion, passing through Subjects were examined daily for swell-a third point corresponding to themandibular third molar on the ing, and the measurements were reported inoutside part of the cheek (bro- millimeters to determine changes comparedken line, A). The second was to the basal level at the beginning of thefrom the lower ear lobe to thelabial commissure (solid line, B). study, which was equal to zero. The obser- vation was that neither Rheumazin nor Feldene inhibited the swelling induced by the surgical procedure, a fact that became evident at the 6th hour. Thus, both drugs were similar regarding the control of facial swelling that persisted until the 120th hourFigure 2. Time response curve (R = 5.03; 3.31-7.62), compared to Feldenefor the development of postop-erative pain as measured on a (F = 4.90; 2.18-5.90).visual analogue scale. Patients In addition, at each visit, patients receiv-receiving Feldene or Rheumazin ing Feldene or Rheumazin were asked towere asked to report the inten-sity of pain indicating a visual report any discomfort during the study, be-analogue scale score of 0 to 10 sides adverse effects. Patients who receivedat 6, 24, 48, 72, and 120 h after Feldene reported a larger number of adversethe surgical procedure. Data arereported as mean ± SEM score. effects, including headache (N = 3); gastric*P < 0.05 (two-way ANOVA; t- distress and nausea (N = 2); sudorese, chillstest) and fever (N = 3); sleepiness and paresthesiasBraz J Med Biol Res 39(9) 2006
    • Efficacy and safety of combined piroxicam treatment 1245(N = 2), while only one patient who received Feldene, and is combined with a lower doseRheumazin reported moderate gastric pain. of dexamethasone (1 mg) along with orphe- At the end of the study, patients were nadrine as a muscle relaxant and cyanoco-asked to evaluate the treatment with regard balamin to improve nerve preservation. Theto pain and swelling. The patients could rate use of drug combinations aimed at increas-the efficacy of the drug as poor, moderate, ing the therapeutic potency and reducing thegood, very good, or excellent. The Rheu- occurrence of possible adverse reactions ismazin group had higher scores than the justified in order to improve patient treat-Feldene group, with 95% of excellent (scores ment (21).3 and 4) or very good scores compared to Therefore, the combination of piroxicam,79.5% (scores 3 and 4) for the Feldene group. dexamethasone, orphenadrine, and cyano-However, the difference was not statistically cobalamin may improve the therapeutic re-significant. sponse with regard to analgesic activity and reduction of inflammation (22). The use ofDiscussion NSAIDs in combination with dexametha- sone has been shown to reduce the dose The third molar post-extraction pain is required to obtain the anti-inflammatory ef-one of the most representative models of fect of the latter (23). NSAIDs are also knownacute post-surgical pain, and has been suc- to modulate type III glucocorticoid recep-cessfully used in recent years to assess the tors by increasing their number, which canefficacy of different analgesic drugs (15). potentiate the action of dexamethasone (24).These surgical procedures result in the re- This fact can also explain the therapeuticlease of chemical mediators, increase nerve potency of Rheumazin compared to Feldeneending sensitivity and retention of a protein- in the present trial, even though it containsrich fluid in the extravascular area (16). It half the amount of dexamethasone andhas been reported that post-oral surgery pain piroxicam habitually used in regular treat-is controllable with some NSAIDs such as ments. In this context, orphenadrine couldpiroxicam and other oxicams (17). Never- enhance the muscle relaxant effect of dexa-theless, NSAIDs are sometimes ineffective methasone, while cyanocobalamin couldin preventing swelling associated with pain contribute to the preservation and repair of(18). For this reason, the use of piroxicam nerve cells. It has been demonstrated that 2combined with dexamethasone can be a good mg dexamethasone can reduce pain and canchoice in terms of reducing the respective reduce the need for analgesic drugs afterdrug doses. tonsillectomy (25). The present clinical trial Acceptance of the use of glucocorticoids with Rheumazin showed that the combina-in dentistry to control post-surgical inflam- tion of 10 mg piroxicam requires only 1 mgmation has been marred by concerns about dexamethasone to relieve pain after thirdside effects, adrenal suppression and effi- molar surgery, similar to Feldene, 20 mgcacy. The mode of administration generally piroxicam. In addition, Rheumazin treatmentused is characterized as short-term, high- required less use of escape analgesia afterdose or pulse therapy, which has not been surgery, which can reduce the possibility ofassociated with significant side effects or paracetamol hepatotoxicity (26).adrenal suppression beyond 10 days (19). On the other hand, dexamethasone mayTherefore, the use of steroids may inhibit the reduce the risk of hypersensitivity to piroxi-initial step in this process (20). cam through immunosuppressive events Rheumazin is a drug that contains half leading to the inhibition of phospholipase A2the concentration of piroxicam found in (27). Allergic reactions to NSAIDs may re- Braz J Med Biol Res 39(9) 2006
    • 1246 B.A. Barroso et al. sult in the increased synthesis of leukotri- Rheumazin can also be used for the control enes, thus producing an antagonistic effect of the pain occurring after surgical trauma in on cyclooxygenase activity (28). third molar removal and that it could be a Another event that can be observed after substitute for Feldene when indicated for surgery for third molar removal is muscle postoperative treatment. Our results demon- spasm. Drugs that have muscle-relaxing ac- strated equivalent therapeutic efficacy of tivity combined with NSAIDs and analge- Rheumazin at the dose evaluated when com- sics may reduce muscle spasms after injury- pared to the positive control Feldene. Cor- causing procedures better than when used roborating the conclusion is the fact that alone (29). The synergistic effect of the con- when patients were asked to evaluate their comitant use of dexamethasone and piroxi- treatment, 95% of those in the Rheumazin cam can lead to a reduction in the dose of group gave scores of excellent or very good orphenadrine since only a 35-mg dose is compared to 80% of those in the Feldene present in the Rheumazin formulation (30). group. Regarding the lack of statistical dif- All of the above mentioned events can ference between the effect of the drugs, we contribute to patient recovery by replacing believe that this was probably due to the injured or dead tissue as a step toward wound small number of participants in each group healing (31). Therefore, certain substances of this trial. need to be present at the injured area for Both drugs showed the same effective- optimal cell proliferation (32,33). The pres- ness in the control of pain with Rheumazin ence of cyanocobalamin (vitamin B12) in displaying less adverse effects than Feldene. Rheumazin is important due to its role as a Therefore, Rheumazin may provide a better co-enzyme in DNA synthesis, together with risk/benefit ratio in the mandibular molar the presence of dexamethasone which has surgery. Since the side effects resulting from neuron protective activity (7). NSAID administration are severe limitation The synergism between dexamethasone, to the routine use of these drugs in clinical piroxicam, orphenadrine citrate, and cyano- practice, our results suggest that Rheumazin cobalamin, according to the results obtained can be a good choice for third molar removal in the present trial, leads us to conclude that treatment.References 1. Barden J, Edwards JE, McQuay HJ, Andrew MR. Pain and analge- 7. Pittock SJ, Payne TA, Harper CM. Reversible myelopathy in a 34- sic response after third molar extraction and other postsurgical pain. year-old man with vitamin B12 deficiency. Mayo Clin Proc 2002; 77: Pain 2004; 107: 86-90. 291-294. 2. Khan AA, Brahim JS, Rowan JS, Dionne RA. In vivo selectivity of a 8. Hillman RS. Hematopoietic agents: growth factors, minerals, and selective cyclooxygenase 2 inhibitor in the oral surgery model. Clin vitamins. In: Hardman JG, Limbird LE, Gilman AG (Editors), Pharmacol Ther 2002; 72: 44-49. Goodman and Gilman’s the pharmacological basis of therapeutics. 3. Desjardins PJ. Analgesic efficacy of piroxicam in postoperative 10th edn. New York: McGraw Hill; 2001. p 1487-1517. dental pain. Am J Med 1988; 84: 35-41. 9. Patel A, Skelly AM, Kohn H, Preiskel HW. Double-blind placebo- 4. Vane J, Botting R. Inflammation and the mechanism of action of anti- controlled comparison of the analgesic effects of single doses of inflammatory drugs. FASEB J 1987; 1: 89-96. lornoxicam and aspirin in patients with postoperative dental pain. Br 5. Vane JR, Botting RM. Mechanism of action of anti-inflammatory Dent J 1991; 170: 295-299. drugs. Scand J Rheumatol Suppl 1996; 102: 9-21. 10. Susarla SM, Dodson TB. Estimating third molar extraction difficulty: 6. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of a comparison of subjective and objective factors. J Oral Maxillofac skeletal muscle relaxants for spasticity and musculoskeletal condi- Surg 2005; 63: 427-434. tions: a systematic review. J Pain Symptom Manage 2004; 28: 140- 11. Garcia AG, Sampedro FG, Rey JG, Vila PG, Martin MS. Pell-Gre- 175. gory classification is unreliable as a predictor of difficulty in extract-Braz J Med Biol Res 39(9) 2006
    • Efficacy and safety of combined piroxicam treatment 1247 ing impacted lower third molars. Br J Oral Maxillofac Surg 2000; 38: swelling after removal of impacted third molars. J Oral Maxillofac 585-587. Surg 1995; 53: 2-7.12. Walton GM, Rood JP, Snowdon AT, Rickwood D. Ketorolac and 23. Hirschelmann R, Poch G, Rafler I, Rickinger O, Giessler J. Steroid- diclofenac for postoperative pain relief following oral surgery. Br J saving potency of nonsteroidal antiinflammatory agents - a reevalu- Oral Maxillofac Surg 1993; 31: 158-160. ation with the new agent CGP 28238 in rat inflammatory models.13. Hyrkas T, Ylipaavalniemi P, Oikarinen VJ, Paakkari I. A comparison Agents Actions Suppl 1991; 32: 51-57. of diclofenac with and without single-dose intravenous steroid to 24. Golikov PP, Nikolaeva NI, Marchenko VV. Nonsteroidal antiinflam- prevent postoperative pain after third molar removal. J Oral matory agents as modulators of glucocorticoid function of receptors. Maxillofac Surg 1993; 51: 634-636. Vestn Ross Akad Med Nauk 1994; 47-52.14. O’Brien TP, Roszkowski MT, Wolff LF, Hinrichs JE, Hargreaves KM. 25. Stewart R, Bill R, Ullah R, McConaghy P, Hall SJ. Dexamethasone Effect of a non-steroidal anti-inflammatory drug on tissue levels of reduces pain after tonsillectomy in adults. Clin Otolaryngol Allied Sci immunoreactive prostaglandin E2, immunoreactive leukotriene, and 2002; 27: 321-326. pain after periodontal surgery. J Periodontol 1996; 67: 1307-1316. 26. Meredith TJ, Vale JA. Non-narcotic analgesics. Problems of over-15. Olmedo MV, Vallecillo M, Gálvez R. Relación de las variables del dosage. Drugs 1986; 32 (Suppl 4): 177-205. paciente y de la intervención con el dolor y la inflamación postopera- 27. Goppelt-Struebe M. Molecular mechanisms involved in the regula- torios en la exodoncia de los terceros molares. Med Oral 2002; 7: tion of prostaglandin biosynthesis by glucocorticoids. Biochem 360-369. Pharmacol 1997; 53: 1389-1395.16. Roszkowski MT, Swift JQ, Hargreaves KM. Effect of NSAID admin- 28. Beutler B. TNF, immunity and inflammatory disease: lessons of the istration on tissue levels of immunoreactive prostaglandin E2, leuko- past decade. J Investig Med 1995; 43: 227-235. triene B4, and (S)-flurbiprofen following extraction of impacted third 29. Hunskaar S, Donnell D. Clinical and pharmacological review of the molars. Pain 1997; 73: 339-345. efficacy of orphenadrine and its combination with paracetamol in17. Hart FD, Huskisson EC. Non-steroidal anti-inflammatory drugs. Cur- painful conditions. J Int Med Res 1991; 19: 71-87. rent status and rational therapeutic use. Drugs 1984; 27: 232-255. 30. Troullos ES, Hargreaves KM, Butler DP, Dionne RA. Comparison of18. Ferreira SH. Peripheral analgesic sites of action of anti-inflamma- nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen, tory drugs. Int J Clin Pract Suppl 2002; 2-10. with methylprednisolone and placebo for acute pain, swelling, and19. Gersema L, Baker K. Use of corticosteroids in oral surgery. J Oral trismus. J Oral Maxillofac Surg 1990; 48: 945-952. Maxillofac Surg 1992; 50: 270-277. 31. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid defi-20. Montgomery MT, Hogg JP, Roberts DL, Redding SW. The use of ciency associated with point mutation in the adrenocorticotropin glucocorticosteroids to lessen the inflammatory sequelae following receptor. Lancet 1993; 341: 461-462. third molar surgery. J Oral Maxillofac Surg 1990; 48: 179-187. 32. Weissbach H, Taylor RT. Metabolic role of vitamin B12. Vitam Horm21. Kaitin KI, Manocchia M, Seibring M, Lasagna L. The new drug 1968; 26: 395-412. approvals of 1990, 1991, and 1992: trends in drug development. J 33. Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose Clin Pharmacol 1994; 34: 120-127. methylcobalamin promotes nerve regeneration in experimental acryl-22. Schultze-Mosgau S, Schmelzeisen R, Frolich JC, Schmele H. Use amide neuropathy. J Neurol Sci 1994; 122: 140-143. of ibuprofen and methylprednisolone for the prevention of pain and Braz J Med Biol Res 39(9) 2006