ORIGINAL ARTICLE Is dipyrone effective as a preemptive analgesic in third molar surgery? A pilot study Vinícius Tatsumoto Favarini1 & Carlos Alysson Aragão Lima1 & Rogério Almeida da Silva2 & Fábio Ricardo Loureiro Sato3 Received: 29 April 2017 /Accepted: 28 December 2017 /Published online: 20 January 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Purpose Studies on preemptive analgesia in maxillofacial surgery have shown several controversial clinical results, mainly due to the absence of a methodological standard, besides a wide variety of studied drugs. This study intended to answer the following hypothesis: Is the administration of dipyrone preemptively capable of decreasing trans- and postoperative pain in the third molar surgical extraction? Methods A pilot prospective double-blind placebo-controlled study was carried out with 25 patients submitted to the third molar surgical extraction at two moments, one side in each intervention. Dipyrone (1 g) was preemptively administered (study group) for the extraction of two third molars on the same side and, in a second surgical procedure, dipyrone (1 g) was administered in the immediate postoperative period (control group). Evaluated variables were the amount of anesthetic, pain perceived through the visual analogue scale (VAS) in transoperative and immediate postoperative periods, and over 12-h investigation period, analgesic consumption, duration of surgery, and time to rescue analgesia. Results The results were submitted to Student’s t test and statistical differences were observed in transoperative (p < 0.05) and immediate postoperative (p < 0.01) periods, while the other studied variables did not present statistical differences. Conclusion The preemptive administration of dipyrone decreased the perception of transoperative and immediate postoperative pain when compared to its use after surgery only. Keywords Third molar surgery . Preemptive analgesia . Dipyrone Introduction The concept of preemptive analgesia, reported classically by Patrick Wall in 1988, consists of the reduction of postopera- tive pain through drug administration prior to surgical trauma. According to some studies, when painful peripheral stimuli are transmitted to the central nervous system (CNS), the process of central sensitization, named neural plasticity, oc- curs and contributes to hyperalgesia and postoperative allodynia [1–3]. Since the generation and the maintenance of pain are com- plex and multicentric processes, this chain can be interfered with at three different levels through the pharmaceutical groups: anesthetics, anti-inflammatory drugs, and analgesics. Local anesthetics are effective in preventing the spread of impulses from the peripheral nervous system to the CNS. However, tissue injury locally promotes the release of inflam- matory chemical mediators through a cascade, mainly that of prostaglandins. Anti-inflammatory drugs act in this level, inhibiting the formation of prostaglandins, either by inhibiting the enzyme cyclooxygenase by the nonsteroidal anti- inflammatory drugs (NSAIDs) or by inhibiting phospholi- pases A2 (corticosteroids) [2, 4, 5]. Studies involving animals have been quite favorable to the applicability of this concept. However, clinical studies in humans have shown controversial results due to (1) a wide variety of evaluated drugs and (2) the lack of methodological * Fábio Ricardo Loureiro Sato fabio.sato@ict.unesp.br 1 Resident of Oral and Maxillofacial Surgeon, Hospital Geral de Vila Penteado, São Paulo, Brazil 2 Chief of Oral and Maxillofacial Surgery Department, Hospital Geral de Vila Penteado, São Paulo, Brazil 3 Department of Oral and Maxillofacial Surgery State University of São Paulo UNESP, College of Dentistry São José dos Campos and Oral andMaxillofacial Surgeon, Hospital Geral de Vila Penteado, Av. Eng. Francisco José Longo, 777, São José dos Campos, SP 12245-000, Brazil Oral and Maxillofacial Surgery (2018) 22:71–75 https://doi.org/10.1007/s10006-018-0669-y http://crossmark.crossref.org/dialog/?doi=10.1007/s10006-018-0669-y&domain=pdf mailto:fabio.sato@ict.unesp.br standard (surgical size, type of anesthesia, and mode of drug administration). Thus, the clinical applicability of preemptive analgesia in the third molar surgical extraction requires further studies [1–7]. Dipyrone acts on the CNS mainly through N-methyl-D- aspartate (NMDA) glutamate receptor antagonism and periph- eral action, by the blockade of calcium influx into the noci- ceptor [8]. This mechanism of action is interesting to the use in preemptive analgesia, so that preoperative dipyrone adminis- tration leads to an increase in pain threshold in the transoperative period. Dipyrone would be able to decrease the pain sensitization in the transoperative period, providing less discomfort during surgery, as well as in the postoperative period through the blockade of central sensitization, with low- er consumption of anesthetics in the transoperative period and analgesics in the postoperative one. Despite this bivalent mechanism of action, studies on the preemptive analgesia of dipyrone in oral and maxillofacial surgeries have not been carried out. Thus, the present study intended to answer the following hypothesis: Is the administration of dipyrone preemptively capable of decreasing trans- and postoperative pain in the third molar surgical extraction, as well as the use of anesthetic drugs postoperatively? Material and method A pilot prospective double-blind placebo-controlled study was carried out. A total of 36 patients who sought the service of oral and maxillofacial surgery of the General Hospital BDr. José Pangella de Vila Penteado,^ São Paulo, SP, Brazil, for the ex- traction of the four thirdmolars were selected. Among inclusion criteria, teeth should be totally inside the bone and symmetri- cally between both sides; patients could not report a prior aller- gy to the drugs used in this study and should be classified according to the American Society of Anesthesiologists (ASA) at ASA I or II. Patients with coagulopathy and pregnant and breastfeeding women were excluded. In addition, the pa- tient could not have an inflammation or infection in the local of the surgery, since they would sensitize the CNS and interfere with preemptive analgesia. Patients were submitted to the third molar surgical extrac- tion at twomoments, with two teeth on the same side (superior and inferior) removed in each intervention. An interval of at least 2 months was given between surgeries in order to ensure that the healing process would not interfere with the preemp- tive analgesia of the second operated side. All surgeries were performed by the same surgeon (VTF). Thus, on one operated side (study side), dipyrone was ad- ministered preoperatively, and in the other side (control side), dipyrone was administered in the immediate postoperative period, so that all patients were treated with both groups. The choice of the first side to be operated (study or control) was made in a random and double-blind manner, where nei- ther the surgeon nor the patient had access to this information. Subsequently, the results were grouped according to the use of dipyrone pre- or postoperatively, which consisted of the study group and the control group, respectively. The drug protocol was identical in both surgical times, only with change in dipyrone administration (preoperatively or im- mediate postoperatively). Thus, 1 g cefazolin (intravenous, IV) and 8 mg dexamethasone (IV) were administered in all patients. In the study side, 1 g dipyrone diluted in 10 ml saline solution (IV) was administered, while only 10 ml saline solu- tion (IV) was administered in the control side. In immediate postoperatively administration, 10 ml saline solution (IV) was administered in the study side, while 1 g dipyrone diluted in 10 ml saline solution (IV) was administered in the control side. After surgery, all patients were treated with 50 mg diclofenac sodium for 3 days and 0.12% chlorhexidine digluconate for 7 days. They were advised to use 1 g dipyrone in case of pain (rescue drug). The use of dipyrone was record- ed during the postoperative period, consisting of an indirect indicator of the amount of postoperative pain. In order to evaluate the pain during surgery, the anesthetic technique and the number of used tubes were standardized as follows. For upper third molar extraction, posterior superior alveolar and palatine nerves were blocked through one anes- thetic tube, each one containing 1.8 ml prilocaine 3% with 0.03 IU felipressine. For the extraction of inferior third molars, the pterygomandibular anesthetic technique was used to anes- thetize inferior alveolar, lingual, and buccal nerves, with a total of two anesthetic tubes (3.6 ml). The need for anesthetic complementation was a quantitative variable of transoperative pain, in which the amount (total or fractional) of tubes re- quired for effective anesthesia was recorded. The technique was standardized in all surgeries: pterygomandibular access, peripheral ostectomy, odontosection (when necessary), luxation, avulsion, curettage, abundant irri- gation with 0.9% saline solution, and suture. At the end of surgery, patients received the respective med- ications and were submitted to a questionnaire containing the visual analogue scale (VAS), in which they were instructed to fill in with a score that best expressed the amount of pain felt at a certain time. Pain was recorded through VAS at eight pe- riods: transoperative, immediately after surgery, and at 1, 2, 4, 6, 8, and 12 h after surgery. In addition, patients received a table in which they were advised to record the day and the time when they needed to be medicated with dipyrone for analgesic control in the postop- erative period. The last studied variable consisted of the period between the end of surgery and the beginning of pain that required the use of dipyrone, named rescue drug time. 72 Oral Maxillofac Surg (2018) 22:71–75 Moreover, surgical duration was recorded and compared between study and control groups. The protocol of this study was approved by the local re- search ethics committee under number 44982115.2.0000.5446 and informed consent forms were obtained from all participat- ing patients. Results From a total of 36 patients included in the study, 9 of them were excluded due to incomplete data at any study period, 1 of them was excluded due to a postoperative complication (alveolitis) and another one was excluded due to inconsistent data. The data of 25 patients were submitted to descriptive statistics and then to Student’s t test (Table 1). Demographic variables such as gender, age, and weight are described in Table 1. The results of both groups regarding the administered amount of local anesthetic, surgical duration, postoperative analgesic consumption, and the pain perceived by VAS from the transoperative period to 12 h after surgery are shown in Fig. 1 and Table 2 (95% confidence level, p < 0.05). When comparing the use of dipyrone preemptively and postoperatively, statistically significant differences (p < 0.05) were observed only in pain represented by VAS in transoperative and immediate postoperative periods. No differences were found when evaluating the adminis- tered amount of local anesthetic and surgical duration (Table 2). Furthermore, results regarding rescue drug time are shown in Fig. 2. No differences (p = 0.58) were found in rescue drug time of dipyrone administered before and after surgery. Discussion This study indicated that the administration of dipyrone pre- emptively was more effective than its postsurgical use regard- ing pain perception in transoperative and immediate postop- erative periods, with no impacts on the use of anesthetics in the surgical procedure, as well as the use of analgesics in the postoperative period. Studies on preemptive analgesia have been methodologi- cally performed in order to administer only the drug to be studied [9, 10]. A criticism on this work can be made with regard to the coadministration of dexamethasone and dipyrone, probably reducing the analgesic effect of dipyrone compared with its use singly. Several studies have reported the benefit of preemptive dexamethasone in reducing edema and postoperative trismus. The authors stated that the benefits al- ready established by other studies cannot be ignored in the search for better therapeutic options. In this way, preemptive dexamethasone has been chosen for both groups, despite the bias of possible synergistic effect of both drugs [3, 11, 12]. In the literature, studies have evaluated preemptive analge- sia in third molar surgery, with several drugs and protocols. Ong et al. [11] compared the administration of 30 mg ketorolac (IV) preemptively and postoperatively and observed that the preemptive use provided up to 2 h of a better analgesia than that of the postoperative one. On the other hand, some works such as Jung et al. [5] evaluated the oral administration of a NSAID drug (370 mg Table 1 Demographic details of patient’s sample with results expressed as mean ± SD Variable Number of subjects 36 Number of dropouts 11 Male:female 09:16 Age (years) 22.1 ± 4.4 Weight (kg) 61.4 ± 11.7 Fig. 1 Mean pain intensity scores (mm) recorded on VAS throughout the 12-h investigation period for the sides pretreatment and posttreatment with dipyrone sodium Oral Maxillofac Surg (2018) 22:71–75 73 talniflumate) 1 h before the third molar extraction and ob- served no differences in the effectiveness of pain control when compared to its postoperative use. Other studies including that of Kaczmarzyk et al. [13] com- pared the effect of oral administration of ketoprofen (100 mg) on three groups, i.e., 60 min before surgery, 60 min after surgery, and the placebo group, and observed that the use after surgery was the only group taking longer to present painful symptomatology, so that pain intensity was also lower. Ong and Tan [12] compared the preemptive use of ketorolac (30 mg) and tramadol (50 mg) intravenously and observed that the former was more effective in controlling postoperative pain. Bauer et al. [3] evaluated the effect of preemptive analgesia on Ibuprofen administration and did not observe differences when compared to the placebo group. The coadministration with dexamethasone preemptively was more effective in pain control than the placebo group. This same synergistic interaction between dexamethasone and Ibuprofen may have occurred in the present study. Several studies have shown controversial results regarding preemptive analgesia involving the administration of NSAIDs [14]. The effect of talniflumate, diclofenac, aspirin, acetamin- ophen, ibuprofen, and rofecoxib were studied with no stan- dardization, e.g., the administration of the same drug before and after surgery, the evaluation of pain perception, and the use of analgesic after surgery [2, 4, 5, 9]. In this way, the results cannot be compared with each other. Pain perception (VAS) was lower in transoperative and immediate postoperative periods in patients who had used dipyrone preemptively. Theoretically, preoperative admin- istration directly decreased the pain sensitization in such patients. Although both groups of patients have been equally anesthetized at these two moments, the results indicated that pain perception is not only related to an- esthetic blockade, but also is influenced by decreased Table 2 Operation details and efficacy parameters recorded in the investigation. Results are expressed as a mean ± SD and 95% confidence intervals for the mean Variable Pretreated sides Posttreated sides p value Amount of local anesthetic used (ml) 5.90 ± 0.9 6.01 ± 0.9 0.5 Total analgesic consumption (dose) 1.2 ± 1.3 1.4 ± 1.9 0.4 VAS transsurgical (mm) 12.2 ± 14.3 19.9 ± 21.1 0.05 a VAS postsurgical immediate (mm) 0.3 ± 1.0 5.3 ± 9.4 0.01 a VAS postsurgical 1 h (mm) 8.2 ± 13.2 9.1 ± 15.2 0.7 VAS postsurgical 2 h (mm) 8.0 ± 12.4 11.4 ± 16.2 0.3 VAS postsurgical 4 h (mm) 8.8 ± 13.6 11.8 ± 17.6 0.1 VAS postsurgical 6 h (mm) 5.4 ± 8.9 9.5 ± 3.1 0.2 VAS postsurgical 8 h (mm) 6.1 ± 11.0 9.2 ± 19.2 0.4 VAS postsurgical 12 h (mm) 6.8 ± 11.1 12.6 ± 24.4 0.2 Duration of surgery (min) 41.8 ± 14.9 43.9 ± 17.3 0.3 a Significant difference between pretreated and posttreated sides Fig. 2 Time of the rescue drug between pre- and postoperative. DS administered in preoperative (study group) and postoperative (control group), respectively 74 Oral Maxillofac Surg (2018) 22:71–75 central sensitization, which reduces the perception of painful stimuli. No differences were observed regarding rescue drug time in the comparison between groups. This fact is due to the analgesic needs to be used continuously after its half-life re- gardless of its preemptive or non-preemptive administration. Furthermore, dexamethasone has a longer half-life than dipyrone, which may have influenced the results of such a variable. A low amount of anesthetic complementation was ob- served. The technique recommends 5.4 ml per side and the complementation was 0.5 and 0.6 ml on average for study and control groups, respectively (Table 2). This data reinforces the idea that the used drug protocol was efficient and did not interfere with preemptive analgesia. Conclusion The preemptive administration of dipyrone in the third molar surgical extraction was more effective when compared to its postoperative use in the reduction of pain perception in transoperative and immediate postoperative periods. Furthermore, such a drug has advantages including wide availability, low cost, and less side effects than those of anal- gesic drugs such as ketamine, tramadol, and codeine. We rec- ommend its use prior to the beginning of the surgical proce- dure instead of only in the postoperative period, when surgical trauma already sensitized the central neurons. Thus, more comfort can be provided to patients during surgery and shortly after its end. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institu- tional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. References 1. Bromley L (2006) Pre-emptive analgesia and protective premedication. What is the difference? Biomed Pharmacother 60(7):336–340. https://doi.org/10.1016/j.biopha.2006.06.012 2. Gottschalk A, Smith DS (2001) New concepts in acute pain thera- py: preemptive analgesia. Am Fam Physician 63(10):1979–1984 3. Bauer HC, Duarte FL, Horliana AC, Tortamano IP, Perez FE, Simone JL, Jorge WA (2013) Assessment of preemptive analgesia with ibuprofen coadministered or not with dexamethasone in third molar surgery: a randomized double-blind controlled clinical trial. Oral Maxillofac Surg 17(3):165–171. https://doi.org/10.1007/ s10006-012-0360-7 4. Ong CKS, Lirk P, Seymour RA, Jenkins BJ (2005) The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 100(3):757–773. https://doi.org/10. 1213/01.ANE.0000144428.98767.0E 5. Savage MG, Henry MA, Colo D (2004) Preoperative nonsteroidal anti-inflammatory agents: review of the literature. Oral Surg Oral MedOral Pathol Oral Radiol Endod 98(2):146–152. https://doi.org/ 10.1016/j.tripleo.2004.01.012 6. Jung YS, Kim MK, Um YJ, Park HS, Lee EW, Kang JW (2005) The effects on postoperative oral surgery pain by varying NSAID administration times: comparison on effect of preemptive analgesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100(5):559– 563. https://doi.org/10.1016/j.tripleo.2005.02.065 7. Gutta R, Koehn CR, James LE (2013) Does ketorolac have a pre- emptive analgesic effect? A randomized, double-blind, control study. J Oral Maxillofac Surg 71(12):2029–2034. https://doi.org/ 10.1016/j.joms.2013.06.220 8. Cavalcanti IL, Cantinho FAF, Assad A. Medicina Perioperatória (2006). Rio de Janeiro: Sociedade de Anestesiologia do Estado do Rio de Janeiro, 1107–23 9. Neupert EA, Lee JW, Philput CB, Gordon JR (1992) Evaluation of dexamethasone for reduction of postsurgical sequelae of third molar removal. J Oral Maxillofac Surg 50(11):1177–1182. https://doi.org/ 10.1016/0278-2391(92)90149-T 10. Alcantara CEP, Falci SGM, Ferreira FO, Santos CRR, Pinheiro MLP (2014) Pre-emptive effect of dexamethasone and methylpred- nisolone on pain, swelling, and trismus after third molar surgery: a split-mouth randomized triple-blind clinical trial. Int J Oral Maxillofac Surg 43(1):93–98. https://doi.org/10.1016/j.ijom.2013. 05.016 11. Ong KS, Seymour RA, Chen FG, Ho VCL (2004) Preoperative ketorolac has a preemptive effect for postoperative third molar sur- gical pain. Int J Oral Maxillofac Surg 33(8):771–776. https://doi. org/10.1016/j.ijom.2004.01.020 12. Ong KS, Tan JML (2004) Preoperative intravenous tramadol versus ketorolac for preventing postoperative pain after third molar sur- gery. Int J Oral Maxillofac Surg 33(3):274–278. https://doi.org/10. 1006/ijom.2003.0515 13. Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Woron J (2010) Preemptive effect of ketoprofen on postoperative pain fol- lowing third molar surgery. A prospective, randomized, double- blinded clinical trial. Int J Oral Maxillofac Surg 39(7):647–652. https://doi.org/10.1016/j.ijom.2010.02.019 14. Bridgman JB, Gillgrass TG, Zacharias M (1996) The absence of any pre-emptive analgesic effect for non-steroidal anti-inflammato- ry drugs. Br J Oral Maxillofac Surg 34(5):428–431. https://doi.org/ 10.1016/S0266-4356(96)90101-1 Oral Maxillofac Surg (2018) 22:71–75 75 https://doi.org/10.1016/j.biopha.2006.06.012 https://doi.org/10.1007/s10006-012-0360-7 https://doi.org/10.1007/s10006-012-0360-7 https://doi.org/10.1213/01.ANE.0000144428.98767.0E https://doi.org/10.1213/01.ANE.0000144428.98767.0E https://doi.org/10.1016/j.tripleo.2004.01.012 https://doi.org/10.1016/j.tripleo.2004.01.012 https://doi.org/10.1016/j.tripleo.2005.02.065 https://doi.org/10.1016/j.joms.2013.06.220 https://doi.org/10.1016/j.joms.2013.06.220 https://doi.org/10.1016/0278-2391(92)90149-T https://doi.org/10.1016/0278-2391(92)90149-T https://doi.org/10.1016/j.ijom.2013.05.016 https://doi.org/10.1016/j.ijom.2013.05.016 https://doi.org/10.1016/j.ijom.2004.01.020 https://doi.org/10.1016/j.ijom.2004.01.020 https://doi.org/10.1006/ijom.2003.0515 https://doi.org/10.1006/ijom.2003.0515 https://doi.org/10.1016/j.ijom.2010.02.019 https://doi.org/10.1016/S0266-4356(96)90101-1 https://doi.org/10.1016/S0266-4356(96)90101-1 Is dipyrone effective as a preemptive analgesic in third molar surgery? A pilot study Abstract Abstract Abstract Abstract Abstract Introduction Material and method Results Discussion Conclusion References