A triple-blind randomized clinical trial of different associations between dexamethasone and non-steroids anti-inflammatories for preemptive action in third molar extractions Gustavo Antonio Correa Momesso1, Gustavo Augusto Grossi-Oliveira1, William Phillip Pereira Silva1, Renan Akira2, Fernando Chiba2, Tárik Ocon Braga Polo1, Tiburtino José de Lima Neto1, Bárbara Ribeiro Rios1, Ana Paula Farnezi Bassi1, Doris Hissako Sumida2, Michael Han3, Michael Miloro3 & Leonardo Perez Faverani1 Scientific Reports 11, Article number: 24445 (2021) Cite this article Oral analgesicsClinical trial design The aim of this study is to evaluate the preemptive analgesic effects of dexamethasone (DEX) alone or combined with non-steroidal anti-inflammatory drugs (NSAIDs) in third molar surgeries. The subjects were divided into five groups (n = 20 teeth/group); subjects received only 8 mg of dexamethasone 1 h before the surgical procedure (DEX group), or in combination with etodolac (DEX + ETO), ketorolac (DEX + KET), ibuprofen (DEX + IBU), loxoprofen (DEX + LOX). Paracetamol 750 mg was provided as the number of rescue analgesics (NRA). Salivary PGE2 expression was measured preoperatively and at 48 h. Edema and Maximum mouth opening (MMO) were measured postoperatively at 48 h and 7 days. A visual analog scale (VAS) was performed postoperatively at 6, 12, 24, 48, 72 h, and 7 days. Salivary expression of PGE2 showed a decrease only for the DEX group. Edema and MMO and NRA consumption showed no significant differences among the groups (P > 0.05). The VAS showed a significantly lower pain perception at 6 h after the surgery for the DEX + ETO and DEX + KET groups (P < 0.05). The combination of DEX and NSAIDS should be considered for preemptive acute postsurgical pain management in third molar surgery. In some drug associations such as dexamethasone 8 mg + NSAIDS (ETO and KET) in the pre-operative time, only a few rescue analgesics are necessary.
Postoperative pain and edema remain significant concerns for patients who undergo third molar removal. For this reason, the literature contains several studies about controlling these symptoms1. It is the responsibility of the surgeon to treat the postoperative symptoms of challenging third molar surgeries, which can be quite intense, limiting patients’ daily routines, and causing considerable discomfort2,3.Thus, preoperative drug therapies have been suggested to prevent or relieve postoperative symptoms3,4. Preemptive analgesia consists of managing drugs prior to nociceptive stimulation and is defined as an anti-nociceptive treatment that prevents the inflammatory response from stimulation of the afferent pathway to the central nervous system. This general mechanism is responsible for the amplification of the postoperative pain response5.Steroidal anti-inflammatory drugs (e.g. corticosteroids) are used extensively during the preoperative period prior to third molar surgery. Several authors have demonstrated the efficacy of these drugs, mainly in the control of postoperative edema and trismus (MMO)6,7,8,9. This effect is achieved because corticosteroids inhibit the conversion of phospholipids into arachidonic acid by phospholipase A2. This mechanism is responsible for preventing the production of leukotrienes, prostacyclins, prostaglandins, and thromboxane A2, which mediate pain and inflammation. The use of corticosteroids is believed to inhibit the initial step in this process6.Nonsteroidal anti-inflammatory drugs (NSAIDs) are mostly used during the postoperative period of third molar surgeries due to their considerable anti-nociceptive effects10,11,12. Its mechanism of action consists of inhibiting the cox enzymes, in a specific or non-specific way depending on the drug of this selected class, leading to a decrease in the production of prostaglandins, in addition to inhibiting specific proteinases involved in the degradation of proteoglycans and cartilage collagen, they also inhibit the production of oxygen radicals and bradykinin release, as well as the lymphocyte response to antigenic stimulation, phagocytosis, and granulocyte and monocyte chemotaxis consider inflammation and its symptoms considerably13. However, recent studies have demonstrated that the preemptive combination of NSAIDs and corticosteroids seems to improve the relief of postoperative symptoms after third molar surgeries, mainly in the acute postoperative period4,14,15. A possible explanation for the efficacy of this combination is that when administered before surgical trauma and the onset of pain, the drugs will be present in the bloodstream at the appropriate levels, and at the appropriate time when pain symptoms begin. In addition, steroidal anti-inflammatory drugs act at the beginning of the inflammation cascade, preventing the formation of arachidonic acid, while non-steroidal anti-inflammatory drugs act by preventing the conversion of arachidonic acid, which by chance was synthesized, into prostaglandins, preventing a succession of cascade events. Thus, it seems appropriate to assess which preventive therapies are most effective and whether their combined use offers any additional benefit by acting at two different times in the inflammation cascade16.Since there is a lack of consensus and few studies regarding the preemptive combination of steroids and NSAIDs aimed at improving the postoperative pain symptoms after third molar surgery, the purpose of this study is to compare the preemptive use of dexamethasone alone, and the combination of dexamethasone with different NSAIDs, in third molar surgeries.This prospective, randomized, triple-blind clinical trial was approved by the Ethical Committee for Human Experimentation from the São Paulo State University—School of Dentistry, Araçatuba—São Paulo, Brazil (number # 88,903,518.4.0000.5420) in 2018. The trial was registered in a Brazilian Clinical Trials Registry (REBEC—date of registration: 14/02/2019—number of registration: #RBR-8rfwnq) and was written in accordance with the CONSORT guidelines (www.consort-statement.org) and the principles for medical research involving human subjects in the 1963 Declaration of Helsinki17. All subjects received the research information through the informed consent process. The patients were initially informed that the research aimed to compare many different drugs usually used in relieving the inflammatory symptoms and pain, and they were not aware about what the drugs were prescribed for. Besides that, all the risks about the surgical procedure were informed such as local and systemic infections, alveolar inferior nerve and lingual paresthesia, facial nerve paralysis due to anesthetic technique, mandibular fracture, bleeding, and other minor risks. After this, the patients were instructed that they could quit the research at any moment. These terms explained the study objectives and justifications, the benefits and risks to which the subjects were exposed, and the other items described in the National Health Council’s Guidelines (Resolution CNS 466/12).Patients and subjectsThis study involved 64 subjects presented as healthy subjects fit with the inclusion criteria (ASA I-II: According to those classified by the American Society of Anesthesiologists ASA II are patients with mild systemic disease. Example: Patient with no functional limitations and a well-controlled disease (eg, treated hypertension, obesity with a BMI below 35, frequent social drinker or cigarette smoker). For this, the authors performed an adequate pre-operative anamnesis, as well as requesting laboratory tests and even medical evaluations, when necessary, to define whether the patient had no functional limitations due to mild comorbidity.), never-smokers, between the ages of 16 and 35 years, with an indication of removal of the mandibular third molars with at least 2/3 of the root formed (Class I or II; Position A/B from Pell and Gregory). All surgical procedures required bony removal and tooth sectioning in order to extract the impacted third molars.Patients evaluated might present with the inclusion criteria established by the authors, which were: (a) Healthy patients with no local and systemic disorders. (b) Aged between 16 and 35 years. (c) Need of removal lower third molars with at least 2/3 of root formation, evaluated by radiographic exam. Besides that, patients which did not present the necessary characteristics to participate in the study were excluded. The criteria were: (a) Patients presented lower third molars on C position, according to Pell & Gregory classification. (b) Local clinical signs which could not indicate the surgical procedure, as pericoronitis, odontogenic cysts and tumors associated or not with the third molar, trauma in the region, or any symptoms that indicate the presence of infection. (c) Presence of any systemic disorder as well diabetes, hypertension, hyperthyroidism, osteoporosis, gastrointestinal diseases that compromise the result of the surgery or any disease which impedes the use of drugs prescribed in this study. (d) Patients which used any drug in the last 30 days previously to the surgical procedure. (e) Patients with hypersensitivity of any drug used in this study. (f) Patients who have intolerance to the other materials that will be used in the research, such as 0.5% alcoholic chlorhexidine solution, 0.12% chlorhexidine gluconate solution and 4% articaine hydrochloride solution with epinephrine 1: 100,000. (g) Female patients which were in the menstrual period or pregnant period and lactation. (The menstrual period causes progesterone to act directly on the neurotransmitters GABA (gamma-aminobutyric acid), opioids, serotonin, and catecholamine, in addition to leading to an increase in prolactin, altering glucose metabolism, the function of the hypothalamic–pituitary–adrenal axis. Even causes insulin resistance and mild nutritional and electrolyte deficiencies that may lead to pain threshold, irritability, and increased fluid retention, which can bias some research analyses 18. Sample size calculationA power test was calculated to obtain the sample size, it was based on a previous pilot study who used pain as a parameter (mean difference = 1.87; standard deviation = 1.75)19, which demonstrated the need for fourteen samples (teeth) for 80% of the power test, the authors added a total of sixteen samples per group. Thus, to obtain more homogeneous data (95% of the power test), 20 samples (teeth) were selected for each group, totaling 60 patients. The test was applied by SigmaPlot 12.0 (Exakt Graphs and Data Analysis, San Jose, CA, USA).Experimental groupsThus, a total of one hundred teeth from 64 subjects were divided into five groups (n = 20): DEX, which represented subjects who received 8 mg of dexamethasone (Laboratório Teuto Brasileiro s/a—17,159,229,000,176, Anápolis, GO, Brazil, code: 12,804—[797728]); DEX + ETO, which represented subjects who received 8 mg of dexamethasone plus 300 mg of etodolac (Laboratório Apsen Farmacêutica, São Paulo, Brazil); DEX + LOX, which represented subjects who received 8 mg of dexamethasone plus 60 mg of loxoprofen (Daiichi Sankyo Brasil, Barueri, Brazil); DEX + KET, which represented subjects who received 8 mg of dexamethasone plus 10 mg of ketorolac (União Química, São Paulo, Brazil); and DEX + IBU, which represented subjects who received 8 mg of dexamethasone plus 600 mg of ibuprofen (Prati Donaduzzi, Toledo, Brazil). All drugs were administered one hour before surgery and administered orally. The surgical interventions were timed from the beginning of the incision until the end of the last suture.RandomizationSubject randomization was performed by a researcher (L.P.F.), who selected groups using the envelope system. The envelope contained papers on which the five groups’ names were written, and a random selection was performed. If the subject presented with two lower third molars, which was compatible with the inclusion criteria, the subject underwent a double draw and could be allocated to two groups. In those cases, another envelope had two papers identifying the side of the mandibular third molar: right or left, determining the sequence of the groups to be operated. The drugs were given to the subjects by the same researcher. All the drugs were manipulated, the capsules were equally the same and were given in a surgical envelope to avoid the recognize of the drug by the patient and create a bias. The surgeon (G.A.C.M.) and the researcher who conducted the analysis (T.O.B.P.) did not know the groups to groups to which the subjects were assigned, characterizing a triple-blind clinical trial.When a subject had bilateral third molars, the choice to initially operate on the right or left side was also determined by the researcher (L.P.F.) using the envelope system. In this situation, the surgeries were conducted unilaterally with a minimum interval of 21 days between the extraction procedures.Surgical proceduresThe surgical procedures were performed by the same surgeon. All subjects received preoperative antibiotic therapy with 2 g of amoxicillin 1 h before the surgical procedure. Intrabuccal antisepsis was performed with vigorous mouth washing for 1 min with an aqueous solution of 0.12% chlorhexidine digluconate, followed by extraoral antisepsis with 0.5% chlorhexidine alcohol solution. The anesthetic technique employed comprised a regional blockade of the inferior alveolar, buccal, and lingual nerves. This was performed using a reflux syringe with a long 27-gauge gingival needle for injection of 2% mepivacaine hydrochloride with epinephrine 1:100,000 (Mepiadre, DFL) at a maximum volume of 4.5 ml, equivalent to 2.5 tubes.A triangular linear flap was made with a number 15 scalpel blade in the distal region of the lower second molar in association with a buccal releasing incision in the mesial aspect of the second molar. Following this, mucoperiosteal detachment was performed with periosteal relief and a retractor was used to expose the operative field. Osteotomy was performed using a model 702 carbide-tipped drill bit mounted on a high-speed pen, in addition to abundant irrigation with sterile saline NaCl 0.9%. Dental removal was completed with curved and straight extractors of the Seldin type (n° 2, 1R, or 1L), followed by caref
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