29 Comparison of the Efficacy of Etoricoxib And

Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36

Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal Comparação da eficácia de Etoricoxib E Ibuprofeno no controle da dor e do trismo após exodontia de terceiros molares inferiores

Adriana Maria Calvo * Vivien Thiemy Sakai * Karin Cristina Silva Modena ** Bella Luna Colombini ** Marcelo Contador Gallina ** Thiago José Dionisio *** José Roberto Pereira Lauris **** Carlos Ferreira Santos **** Abstract Introduction: This work compares the efficacy of two different non-steroidal anti-inflammatory drugs (NSAIDS), etoricoxib (COX-2 selective inhibitor) and ibuprofen (non-selective COX inhibitor), in a double blind, randomized and crossed study, in 16 patients aged 18 years or over who needed the removal of both symmetrically positioned lower third molars. Methods: The following parameters were assessed: 1) subjective postoperative pain evaluation with the aid of a visual analogue scale; 2) mouth opening before the surgery and at the suture removal; 3) incidence, type and severity of adverse reactions, and 4) total amount of rescue medication taken by the patients (paracetamol). Data were analyzed by paired t test and Wilcoxon test. Results: The results revealed that: 1) both NSAIDS were efficient for postoperative pain relief (p>0.05); 2) there was a similar reduction in mouth opening at suture removal compared to the measure in the preoperative period for both NSAIDS (85.34 ± 19.82% and 82.43 ± 15.07% of initial measures for ibuprofen and etoricoxib, respectively, p>0.05); 3) discrete eyelid edema was observed in only one patient medicated with ibuprofen, and 4) there was no statistically significant difference regarding the total amount of rescue medication taken by the patients treated with ibuprofen or etoricoxib (843.75 ± 1189.80 mg and 515.63 ± 808.64 mg, respectively, p>0.05). Conclusion: These data, therefore, suggest that there is no advantage in the prescription of etoricoxib in relation to ibuprofen for pain and trismus reduction after lower third molar removal. DESCRIPTORs: Pain - Trismus - Anti-inflammatory agents, non-steroidal - Molar, third. Resumo

Introdução: Comparar a eficácia de dois antiinflamatórios não-esteroidais (AINES), etoricoxib (inibidor seletivo da cicloxigenase-2) e ibuprofeno (inibidor não seletivo das cicloxigenase-1 e 2), num estudo duplo-cego e cruzado, em 16 pacientes com idade igual ou superior a 18 anos necessitando de exodontia dos dois terceiros molares inferiores (com posições muito semelhantes). Métodos: Avaliaram-se os se- guintes parâmetros: 1) avaliação subjetiva da dor pós-operatória com o auxílio de uma escala analógica visual; 2) abertura de boca antes da cirurgia e no momento da retirada de pontos; 3) incidência, tipo e gravidade das reações adversas e 4) quantidade total de medicação de socorro (paracetamol). Os dados foram analisados pelos testes t pareado e de Wilcoxon. Resultados: Os resultados revelaram que: 1) ambos os AINES se mostraram eficazes para o alívio da dor pós-operatória (p>0,05); 2) houve igual redução da abertura de boca na retirada de pontos em comparação com a medida no período pré-ope- ratório para ambos os AINES (85,34 ± 19,82% e 82,43 ± 15,07% da medida inicial para ibuprofeno e etoricoxib, respectivamente, p>0,05); 3) em relação às reações adversas, apenas 1 paciente medicado com ibuprofeno apresentou edema de pálpebra discreto e 4) não houve diferença significativa com relação à quantidade total de medicação de socorro ingerida pelos pacientes tratados com ibuprofeno ou etoricoxib (843,75 ± 1189,80 mg e 515,63 ± 808,64 mg, respectivamente, p>0,05). Conclusão: Estes dados, portanto, sugerem que não existe vantagem na prescrição do etoricoxib em relação ao ibuprofeno para redução da dor e trismo após extração de terceiros molares inferiores. descritOREs: Dor - Trismo - Antiinflamatórios não esteróides - Terceiro molar.

* Graduate Student, Bauru School of Dentistry, University of São Paulo ** Dentist, Bauru School of Dentistry, University of São Paulo *** Laboratory Technician of Bauru School of Dentistry, University of São Paulo **** Assistant Professor of Bauru School of Dentistry, University of São Paulo

29 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36

Introduction and Literature Review et al.4 2004; Malmstron et al.15,16 2004; Patrignani et al.22 Pain in consequence of third molar surgeries has 2003). Therefore, the aim of this work was to compa- been largely studied and, therefore, became a model to re the clinical efficacy of these two NSAIDS, etoricoxib evaluate the efficacy of many therapeutic approaches in and ibuprofen, for postoperative pain control in lower pharmacological clinic. Frequently, this is a short lasting third molar removal. For this purpose, the experimen- and moderate intensity pain, reaching its maximum tal model of bilateral surgical removal of impacted lower intensity in a short period of time after the end of the third molar teeth was used (Cooper5 1984; Hargreaves e surgery, and, in most cases, patients require some kind Dionne9 1982; Lokken et al.14 1975). of analgesic to treat it (McGrath et al.17 2003). Besides pain, edema and mouth opening limitation associated Methods to the inflammatory response are also undesirable conse- The Ethics Committee of Bauru School of Dentistry, quences to patients who undergo surgical interventions University of São Paulo, approved the protocol of this in oral cavity (Ustun et al. 29 2003). study (process #68/2003). The study population com- For postoperative pain and trismus control resulting prised 16 patients aged 18 year or over, with symmetri- from lower third molar surgeries, several non-steroidal cally positioned full bony impacted lower third molars, anti-inflammatory drugs (NSAIDS) have been used as observed in panoramic radiographies. All patients (Barden et al.1 2004; Ong e Seymour21, 2004; Urquhart28 provided written informed consent during the pretre- 1994). These medications have their therapeutic effect by atment screening period before any study procedures means of the inhibition of cyclooxygenases (COX), whi- were performed. Eligibility criteria included absence of ch determines an inhibition of prostaglandins produc- systemic illness and inflammation or infection at the ex- tion (Smith and Willis27, 1971; Vane 30 1971). However, traction sites. Exclusion criteria included any history of their use has been associated to a great number of adver- allergic reaction to local anesthetic, gastrointestinal ble- se effects, including gastrointestinal ulceration and blee- eding or ulceration, cardiovascular and kidney diseases, ding, inhibition of platelet aggregation and alterations in allergy to aspirin, ibuprofen or any other NSAID. Preg- renal circulation (Brooks at al.2 1999; Kremer13 2000). nant women were also excluded from the study(Khan Two COX isoforms are known: COX-1, a constitutive et al.11 2002; Roszkowski et al.24 1997). Instructions for form expressed in almost all tissues, and COX-2, which not using antidepressant, diuretics or aspirin in the days is predominantly induced and constitutively expressed previous to the surgeries were given to the patients, sin- in a limited number of tissues (renal medulla, prostate, ce these drugs could cause hemorrhage or other blood brain and uterine endothelium) (Komhoff et al.12 1997; problems, thus interfering with the results of this inves- Patrignani et al.22 2003; Smith et al.26 1998; Yamagata tigation. et al.32 1993). Besides, it is believed that COX-2 is the This was a double-blind study, that is, neither the main isoenzyme for pro-inflammatory prostaglandins surgeon nor the patients were aware of the anti-inflam- production (Smith26,1998; Vane31, 1998). Thus, COX- matory agent (etoricoxib or ibuprofen) being tested at 2 selective inhibitor has been largely used in order to the two different appointments. Each patient required selectively inhibit COX-2, but not COX-1, resulting in similar surgical treatment on opposite sides of the man- therapeutic effects comparable to conventional - NSAI dibular jaw, which was performed in two visits 1 to 2 DS, but with less adverse reactions to patients ( Chang months apart (Meechan et al.18 2001).For postoperative et al.4 2004; Daniels at al.6 2002; Khan at al.11 2002; pain relief, in the first appointment the patients- ran Malmstrom et al.15 2004).. domly received either etoricoxib or ibuprofen. In the se- Among NSAIDS used in Dentistry, ibuprofen, a cond appointment, the NSAID not used previously was non-selective COX inhibitor, has been largely studied then administered in a crossed manner. The same surge- (Giles et al.8 1986; Hellman et al.10 1992; Lokken et al.14 on performed all surgeries and postoperative controls. 1975; Malmstron16 2004). In contrast, there are few The patients received a regional anesthetic blockade of data in dental literature concerning the use of etorico- buccal, lingual and inferior alveolar nerves with 1.8 mL xib, a COX-2 selective inhibitor, for postoperative pain of 2% mepivacaine with 1:100,000 adrenaline. When control in patients who undergo dental surgeries (Chang the anesthesia of inferior lip was achieved, additional 0.9

30 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the effi cacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36 mL of the same anesthetic was infi ltrated in the mucosa in order to guarantee hemostasis and anesthesia of the site. Th e administration protocol of etoricoxib was one tablet of 120 mg (Chang et al.4 2004; Malmstrom et al.16 2004; Patrignani et al.22 2003), once daily, while the protocol of ibuprofen was one tablet of 600 mg every 8 hours (tid) (Bugter et al.3 2003; Pohjolainen et al.23 2000). Both NSAIDS were prescribed for 4 days. Res- cue analgesic medication was available to all the patients throughout the study; for this purpose, paracetamol 750 mg was provided to all patients (Norholt et al.19 1995; et al 20 et al 25 Ong . 2004; Schou . 1998). Patients recorded Figure 1 – Pain scores (in mm) recorded by patients (n=16) at the date and time at which rescue medication was taken. 0, 24, 48, 72 and 96 hours. Th ey were also instructed not to interrupt the use of the anti-infl ammatory, even if they had taken rescue analge- cetamol) needed during the postoperative period. sic medication. Since bone tissue removal was necessary in all surgeries, amoxicillin 500 mg was prescribed every All data were properly analyzed by means of graphics 8 hours (tid), for 7 days in order to prevent infection. Table 1 – Duration of surgeries (in min) when patients (n=16) were medicated with ibuprofen and etoricoxib. Th e following parameters were assessed: • Duration of the surgery after anesthetic adminis- Patient Duration of surgery (min) tration (in minutes), which corresponded to the IBUPROFEN ETORICOXIB period between the fi rst incision and the last suture AASC 40 6 et al 29 (Ustun . 2003). ABSL 5 37 • Subjective postoperative pain evaluation, with the AJ 17 15 aid of a 100-mm length visual analogue scale, with 0 anchored by “no pain” and 100 anchored by ANZT 16 9 “worst pain imaginable” (Daniels et al.6 2002; Dio- CSR 5 5 nne et al.7 2001; Hellman et al.10 1992). Subjects DXSQ 7 22 recorded the intensity of postoperative pain at the ELA 5 5 moment in which the studied anti-infl ammatory HMC 10 7 and rescue analgesic medications were taken. JCASC 6 10 • Mouth opening (distance, in mm, between the mesial-incisal corners of the upper and lower right JRM 9 17 central incisors at maximum opening of the jaws) LCSC 5 4 before the surgery and at the moment of suture MAPTP 13 11 removal (5 days postoperatively). Th e postopera- MB 4 5 tive ability to open the mouth was expressed as a PGA 12 19 percentage of preoperative measure (Ustun at al.29 TLM 28 13 2003). WPS 12 10 • Incidence, type and severity of adverse reactions (gastrointestinal irritation, nausea, vomiting, ble- Mean 12.13 12.19 Standard devia- eding, allergy, headache, dizziness, sleepiness and 9.72 8.56 any other kind of reaction) (Daniels et al.6 2002; tion 10 Hellman et al. , 1992). Source: Laboratory of Physiology and Clinical Pharmacology (LAFFIC) • Total amount of rescue analgesic medication (para- from Bauru School of Dentistry – University of São Paulo.

31 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36

Table 2 – Mouth opening (in mm) in pre- and postoperative periods and difference (in %) between both periods for ibuprofen and etoricoxib (n=16). Mouth opening (mm) IBUPROFEN ETORICOXIB Patient Preoperative Postoperative Difference (%) Preoperative Postoperative Difference (%) AASC 58 29 50,00 49 32 65,31 ABSL 40 46 115 50 59 58,00 AJ 48 37 77,08 51 34 66,67 ANZT 48 21 43,75 51 29 56,86 CSR 47 49 104,26 50 47 94,00 DXSQ 53 45 84,91 54 47 87,04 ELA 40 38 95,00 44 44 100,00 HMC 54 52 96,30 54 52 96,30 JCASC 38 33 86,84 38 28 73,68 JRM 51 47 92,16 52 48 92,31 LCSC 48 27 56,25 50 39 78,00 MAPTP 55 48 87,27 56 49 87,50 MB 51 44 86,27 47 3 76,60 PGA 47 43 91,49 45 38 84,44 TLM 40 42 105,00 44 45 102,27 WPS 50 47 94,00 47 47 100,00 Mean 48,00 40,50 85,35 48,88 38,19 82,44 Standard 5,92 8,89 19,83 4,57 12,34 15,07 deviation

Source: Laboratory of Physiology and Clinical Pharmacology (LAFFIC) from Bauru School of Dentistry – University of São Paulo. and tables. The results were presented as the mean ± duration of both surgeries when patients were given standard deviation (SD). Paired t test was used in or- ibuprofen or etoricoxib (p>0.05, Table 1) was observed, der to compare both anti-inflammatory agents. The pa- which permitted a comparative assessment of clinical rameter “rescue analgesic medication” was evaluated by efficacy of both studied NSAIDS. the nonparametric Wilcoxon test. Statistical significance According to the patients’ evaluation on a visual was established at 5%. analogue scale, the reported pain scores were low. In all observed periods, there was no statistically significant di- Results fference in the analgesia promoted by each of the studied Initially, 20 patients were operated. From these, 1 medications (p>0.05, Figure 1). It is important to note patient did not attend the second surgery, and 3 were that the patients ingested ibuprofen every 8 hours, but subjected to 2 surgical procedures with distinct degrees just the times coincident to those of etoricoxib ingestion of difficulty (necessity or not of osteotomy and/or tooth (every 24 hours) were included in Figure 1 for compari- sectioning), despite the fact that both third molars were son. radiographically in similar positions. Due to these rea- There was similar reduction in mouth opening at sons, the final assessment was restricted to the data of the suture removal compared to the preoperative mea- 16 patients. sures for each patient in both treatment groups (85.34 No statistically significant difference in the mean ± 19.82% and 82.43 ± 15.07% of the initial measure

32 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36

Table 3 – Total amount (mg) of rescue analgesic medication experimental model of bilateral surgical removal of im- (paracetamol) ingested by patients (n=16) when they pacted lower third molar teeth is one of the most ac- were medicated with ibuprofen and etoricoxib. cepted methods in dental literature to clinically evaluate the effects of these medications. This method is unique Rescue analgesic medication because, essentially, the same surgery can be performed Patient (paracetamol, mg) twice in the same patient; so that he or she will serve as IBUPROFEN ETORICOXIB his or hers own control, thus avoiding individual res- AASC 3000 0 ponse variations (Cooper5 1984; Hargreaves and Dion- ABSL 0 750 ne9 1992; Lokken et al.14 1975).. Besides, the surgical AJ 750 750 technique and team should be the same in all of the et al 29 ANZT 2250 1500 procedures (Ustun . 2003). In our study, there was no statistically significant difference between the du- CSR 0 0 ration of the first and second surgery (Table 1), which DXSQ 0 750 demonstrates that the t degree of difficulty of the surgi- ELA 0 0 cal procedure and the trauma locally caused were simi- HMC 750 750 lar in both operated sides. Consequently, the resulting JCASC 750 0 inflammation was probably of the same magnitude in JRM 0 0 these sites, and, therefore, the only variable in the study was the anti-inflammatory agent used after each surgery LCSC 3750 3000 (600 mg ibuprofen or 120 mg etoricoxib), making pos- MAPTP 750 0 sible to compare their efficacy for postoperative pain and MB 1500 0 trismus control after the surgeries. PGA 0 0 The analgesic efficacy of the anti-inflammatory dru- TLM 0 750 gs, performed by using the visual analogue scale, showed WPS 0 0 low pain complaint by patients in both postoperative periods, with the use of both 120 mg etoricoxib and 600 Mean 843.75 515.63 mg ibuprofen. Thus, there was no statistically signifi- Standard 1189.80 808.64 cant difference between both drugs during the period deviation of evaluation (Figure 1). In contrast, Malmstrom et al.16 Source: Laboratory of Physiology and Clinical Pharmacology (LAFFIC) from (2004) observed that the proportion of patients who re- Bauru School of Dentistry – University of São Paulo. ceived only one dose of 400 mg ibuprofen and felt low or no pain (15%), after 24 hours of the ingestion of the for ibuprofen and etoricoxib, respectively; p>0.05, Table medicine, was lower than that of patients who received 2). Regarding the adverse reactions to both medications, 120 mg etoricoxib (67%). This disagreement between there was only an allergic reaction (discrete eyelid ede- the results occurred due to the different protocols of ma) in one patient medicated with ibuprofen, two hours ibuprofen prescription, since in our study this drug was after the ingestion of the first dose. However, the inter- administered three times daily (every 8 hours), which is ruption of the drug ingestion was not necessary. consistent to the duration of its effect16. There was no statistically significant difference con- With regard to the mouth opening in both preopera- cerning the total amount of rescue analgesic medication tive periods, the results showed that there was no statis- (paracetamol) ingested by patients treated with ibupro- tically significant difference between these values, which fen or etoricoxib (843.75 ± 1189.5 mg and 515.62 ± demonstrates that all patients recovered totally after the 808.5 mg, respectively; p>0.05, Table 3). first surgery, irrespective of the anti-inflammatory -em Discussion ployed. Additionally, there was no statistically significant In order to investigate the therapeutic efficacy of difference regarding the mouth opening limitation in anti-inflammatory drugs, every effort should be made the moment of suture removal (Table 2). to standardize the procedure (Ustun et al.29 2003). The Etoricoxib and ibuprofen are often well tolerated by

33 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36 patients with pain complaint after dental surgery (Chang coxib, in the model of bilateral removal of lower third 4 16 22 et al. 2004; Malmstron et al. 2004; Patrignani et al. molars, mainly taking into account the high cost of this 2003). In our study, no clinically significant adverse re- drug in comparison to the conventional NSAIDS such action could be observed. Only one patient presented a as ibuprofen. discrete eyelid edema after the administration of ibuprofen. However, neither the interruption of oral intake of Conclusion this NSAID nor the institution of a specific treatment Our data suggest that there is no advantage in the for such allergic response was necessary. It is reasonable prescription of etoricoxib in comparison to ibuprofen to mention that when this patient received etoricoxib, for pain and trismus control in the experimental model neither signs nor symptoms of allergy were observed. of bilateral surgical removal of impacted lower third mo- The patients ingested a very small amount of res- lar teeth. cue analgesic medication (paracetamol), regardless of the NSAID used in the postoperative period (Table 3), Acknowledgments which might be expected due to the low pain complaint reported by the patients (Figure 1). Adriana M. Calvo was supported by a fellowship The clinical efficacy of both NSAIDS could be ob- from CNPq (105862/2002-9). We would like to express served through the assessment of all parameters studied. our gratitude to Sydney José Bruno, manager physician Taken together, our data strengthen the suggestion that of Farmasa, for kindly donating ibuprofen. We also there are no sufficient clinical advantages for the pres- thank Vera Lúcia Rufino Rosa for her excellent secreta- cription of a COX-2 selective inhibitor, such as etori- rial assistance.

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34 Calvo AM, Sakai VT, Modena KCS, Colombini BL, Gallina MC, Dionisio TJ, Lauris JRP, Santos CF. Comparison of the efficacy of Etoricoxib and Ibuprofen in pain and trismus control after lower third molar removal. Revista de Odontologia da Universidade Cidade de São Paulo 2006 jan-abr; 18(1)29-36

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