Preemptive use of intravenous ibuprofen to reduce postoperative pain after lower third molar surgery: a systematic review of randomized controlled trials Pedro Urquiza Jayme Silva0000-0000-0000-0000 ,I Daniela Meneses-Santos0000-0000-0000-0000 ,II Walbert de Andrade Vieira0000-0000-0000-0000 ,III Juliana Cama Ramacciato0000-0000-0000-0000 ,IV Ricardo Pedro da Silva0000-0000-0000-0000 ,I Marcelo Caetano Parreira da Silva0000-0000-0000-0000 ,V Sigmar de Mello Rode0000-0000-0000-0000 ,VI Luiz Renato Paranhos0000-0000-0000-0000 VII,* IProgram de Pos-Graduacao em Odontologia, Faculdade de Odontologia, Universidade Federal de Uberlandia, Uberlandia, MG, BR. II Programa de Residencia, Departamento de Cirurgia e Traumatologia Buco-Maxilo-Facial, Faculdade de Odontologia, Universidade Federal de Uberlandia, Uberlandia, MG, BR. IIIDepartamento de Odontologia Restauradora, Divisao de Endodontia, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas (UNICAMP), Piracicaba, SP, BR. IVDepartamento de Farmacologia, Anestesiologia e Terapeutica, Faculdade de Medicina e Odontologia e Centro de Pesquisas Odontologicas Sao Leopoldo Mandic, Campinas, SP, BR. VDepartamento de Cirurgia e Traumatologia Buco-Maxilo-Facial, Faculdade de Odontologia, Universidade Federal de Uberlandia (UFU), Uberlandia, MG, BR. VIDepartamento de Materiais Odontologicos e Protese, Instituto de Ciencia e Tecnologia, Universidade Estadual Paulista Julio de Mesquita Filho, Campus Sao Jose dos Campos, Sao Jose dos Campos, SP, BR. VIIArea de Odontologia Preventiva e Social, Faculdade de Odontologia, Universidade Federal de Uberlandia (UFU), Uberlandia, MG, BR. Silva PUJ, Meneses-Santos D, Vieira WA, Ramacciato JC, Silva RP, Silva MCP, et al. Preemptive use of intravenous ibuprofen to reduce postoperative pain after lower third molar surgery: a systematic review of randomized controlled trials. Clinics (Sao Paulo). 2021;76:e2780 *Corresponding author. E-mail: paranhos.lrp@gmail.com This study aimed to systematically review the literature to assess the effect of preemptive intravenous ibuprofen on pain reduction after lower third molar surgery. Nine databases (PubMed, Scopus, LILACS, SciELO, Embase, Web of Science, Cochrane, Open Gray, and Open Thesis) were used as sources of research, including ‘‘grey literature.’’ The protocol was registered in PROSPERO. Only randomized clinical trials evaluating the effects of preemptive intravenous ibuprofen on pain during and immediately after the extraction of lower third molars were included, without restrictions of year and language. Two reviewers independently performed the study selection, data extraction, and assessment of the risk of bias. The ‘‘Joanna Briggs Institute for Randomized Controlled Trials’’ tool was used to assess the risk of bias. Each study was categorized according to the percentage of positive responses to the questions corresponding to the assessment instrument. The results were measured narratively/descriptively. The initial search resulted in 3,257 records, of which only three studies (n=150 participants) met the eligibility criteria and were included in the qualitative analysis. All studies were published in 2019. The risk of bias ranged from low to moderate. Two studies found significant pain reduction within 48 h after the procedure. In conclusion, the use of preemptive intravenous ibuprofen for extracting third molars reduces pain and analgesic consumption after the surgical procedure. KEYWORDS: Intravenous Ibuprofen; Ibuprofen; Third Molar Surgery; Preemptive Analgesia; Pain; Postoperative Pain. ’ INTRODUCTION Surgical removal of the third molars is one of the most common procedures in oral surgery (1). It can cause trauma to soft tissues and the bone, resulting in a postoperative inflammatory process in response to pain, edema, and trismus (2). The control of postoperative pain after the removal of third molars has attracted significant interest in scientific literature (2–4). Preemptive analgesia is the concept of a preoperative antinociceptive approach that prevents or modulates postoperative pain (5,6). Preemptive analgesia using non-steroidal anti-inflammatory drugs (NSAIDs) in third molar surgeries has been effective (7–9). NSAIDs inhibit the cyclooxygenase (COX), COX-1, and COX-2 enzymes, reducing the production of prostaglandins that contribute to the peripheral and central sensitization of inflammatory pain (10). COX-1 is physiologically active throughout the body, while COX-2, in addition to some physiological functions, mediates the elevation of prosta- glandins, associated with inflammation, pain, and fever (11). Among the drugs used preemptively to control post- operative pain in third molar surgery are diclofenac (12), ketoprofen (13), lornoxicam (8), and ibuprofen (14,15). Ibuprofen is a non-selective inhibitor of COX-1 and COX-2, which inhibits the formation of inflammatory mediators via the arachidonic acid cascade (16).DOI: 10.6061/clinics/2021/e2780 Copyright & 2021 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. No potential conflict of interest was reported. Received for publication on January 13, 2021. Accepted for publi- cation on May 25, 2021 1 REVIEW ARTICLE https://orcid.org/0000-0002-4146-478X https://orcid.org/0000-0002-8898-9508 https://orcid.org/0000-0001-8872-2865 https://orcid.org/0000-0002-3081-1504 https://orcid.org/0000-0003-4505-2640 https://orcid.org/0000-0001-6010-8062 https://orcid.org/0000-0002-4261-4217 https://orcid.org/0000-0002-7599-0120 mailto:paranhos.lrp@gmail.com https://doi.org/10.6061/clinics/2021/e2780 The preemptive use of intravenous (IV) ibuprofen to reduce postoperative pain in third molar surgery has been the subject of recent studies (17,18). However, there is no consensus regarding its use in clinical practice. Thus, the present study aimed to evaluate the effect of preemptive IV ibuprofen on postoperative pain in lower third molar extractions. ’ METHODS Protocol and registration The present systematic review was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROS PERO, PROTOCOL: CRD42020210477) and performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines (www. prisma-statment.org) (19) and the Joanna Briggs Institute (JBI) guidelines (20). Study design and eligibility criteria This systematic review was based on the research question based on the PICO acronym, described as follows: ‘‘Is the use of preemptive IV ibuprofen (Intervention) more effective in reducing pain (Outcome) when compared to placebo (Comparison) in patients undergoing lower third molar surgery (Population)?’’ The inclusion criteria consisted of randomized controlled trials that compared the preemptive use of IV ibuprofen in patients undergoing extraction of the lower third molars. There were no year- or language-related restrictions. Regarding the degree of difficulty of extraction, there was no restriction in the Pell and Gregory classification, in which the teeth are classified for the ascending mandibular ramus and depth of inclusion in the mandible (21); no relation to Winter classification, which assesses the positioning of the third molar relative to the long axis of the lower second molar (22); or even the type of inclusion (bone, sub-mucous, and semi-included). The exclusion criteria were as follows: 1) studies with patients undergoing extraction of primary teeth; 2) studies without a control group; 3) letters to the editor or editorials; 4) meeting abstracts; and 5) personal opinions, books, and/ or book chapters. Sources of information, search, and selection of studies The search was conducted in May 2020 and updated in March 2021. Seven databases (MEDLINE [via PubMed], Embase, Web of Science, Latin American and Caribbean Literature in Health Sciences, Cochrane, Scielo, and LIVIVO), and two citation databases (Scopus and Web of Science) were used as primary search sources. The Open Gray and Open Thesis databases were used to partially capture the ‘‘grey literature.’’ A manual search was also performed through a systematic analysis of the references of the eligible articles. These steps were performed to minimize selection and publication bias. Medical Subject Headings, Health Sciences Descriptors, and Emtree (Embase Subject Headings) resources were used to select search descriptors. The Boolean operators ‘‘AND’’ and ‘‘OR’’were used to improve the search strategy through various combinations. The search strategies are presented in Table 1. The studies were selected in four stages. In the first stage, studies were identified after bibliographic research in the databases. The results obtained were exported to EndNote Webt software (Thomson Reuters, Toronto, Canada), in which duplicates were removed. The remaining results were exported to Microsoft Wordt 2019 (Microsoft t Ltd, Washington, USA), and duplicate articles were manually removed. Before the second stage, a calibration exercise was perfor- med before the selection of the studies, in which the reviewers discussed the eligibility criteria. In the second stage, a thorough analysis of the study titles was performed. The abstracts were read for the initial application of the eligibility criteria (third stage). In the fourth stage, the preliminary eligible studies had their full texts obtained and evaluated to verify whether they met the eligibility criteria. Data collection A calibration exercise was performed with the two reviewers to ensure consistency between them, in which the information was extracted from an eligible study. After the selection, the studies were analyzed by two reviewers, who extracted the following information from the articles: study identification (author, year, country, and place of research); ethical parameters and use of the consent form for research participants; use of the CONSORT checklist; registration in clinical trials; sample characteristics (study groups, sex, time of preoperative medica- tion administration, postoperative medication schedule, Winter classification, Pell & Gregory, type of inclusion [bone, sub- mucous, and semi-included], tool used for pain assessment); and results (patients excluded, complications, patients who did not return, lost to follow-up, an anesthetic solution used, total loss, and average pain assessment). Risk of individual study bias The JBI Critical Assessment Tool for use in JBI Systematic Reviews for randomized controlled trials (23) was used to assess the risk of bias in the studies selected. Two authors independently assessed each domain relative to the potential risk of bias, as recommended by the PRISMA statement (19). Each study was categorized according to the percentage of positive responses to the questions corresponding to the assessment instrument. The risk of bias was considered high when the study obtained 49% of the answers ‘‘yes,’’ moderate when the study obtained 50–69% of the answers ‘‘yes,’’ and low when the study reached more than 70% of the answer ‘‘yes.’’ Summary measures and summary of results The performance of the studies was measured by evaluat- ing the treatment protocol according to preoperative and postoperative medications, time to assess pain levels, and the use of analgesics during the postoperative period. Pain levels were assessed using a visual analog scale (VAS). For conti- nuous results, descriptive statistics such as mean differences and standard deviations were used to summarize the data from the included studies. The primary outcome of this study was the assessment of pain levels when using ibuprofen intravenously. The final absolute sample size of the patients who underwent extrac- tion of the third molars was established. A meta-analysis was not justified owing to a large amount of clinical, statistical, and methodological heterogeneity. 2 Intravenous ibuprofen to reduce pain Silva PUJ et al. CLINICS 2021;76:e2780 http://www.crd.york.ac.uk/PROSPERO http://www.crd.york.ac.uk/PROSPERO http://www.prisma-statment.org http://www.prisma-statment.org Table 1 - Strategies for database search. Database Search strategy Medline (via PubMed) http://www.ncbi.nlm.nih.gov/ pubmed #1 ("Tooth Extraction*"[MeSH Terms] OR "Tooth Extraction*"[Title/Abstract] OR "Extraction, Tooth"[Title/Abstract] OR "Extractions, Tooth"[Title/Abstract] OR "Oral Surgical Procedures"[MeSH Terms] OR "Oral Surgical Procedures" [Title/Abstract] OR "Surgical Procedures, Oral"[Title/Abstract] OR "Maxillofacial Procedure*"[Title/Abstract] OR ‘‘Third molar’’[Title/Abstract] OR ‘‘Molar, Third’’[MeSH Terms] OR ‘‘Molar, Third’’[Title/Abstract]) #2 ("Ibuprofen"[MeSH Terms] OR "Ibuprofen"[Title/Abstract] OR "Anti-Inflammatory Agent*"[MeSH Terms] OR "Anti- Inflammatory Agent*"[Title/Abstract] OR "Antiinflammatories"[Title/Abstract] OR "Anti-Inflammatories" [Title/Abstract] OR "Anti-Inflammatory Agents, Non-Steroidal"[MeSH Terms] OR "Anti-Inflammatory Agents, Non-Steroidal"[Title/Abstract] OR "NSAIDs"[Title/Abstract] OR "Intravenous Ibuprofen"[Title/Abstract] OR "Cyclooxygenase Inhibitors"[Title/Abstract] OR "Cyclooxygenase Inhibitors"[MeSH Terms]) #1 AND #2 Scopus http://www.scopus. com/ #1 (TITLE-ABS-KEY ("Tooth Extraction*")) OR (TITLE-ABS-KEY ("Extraction, Tooth")) OR (TITLE-ABS-KEY ("Extractions, Tooth")) OR (TITLE-ABS-KEY ("Oral Surgical Procedures")) OR (TITLE-ABS-KEY ("Surgical Procedures, Oral")) OR (TITLE-ABS-KEY ("Maxillofacial Procedure*")) OR (TITLE-ABS-KEY ("Third molar")) OR (TITLE-ABS-KEY ("Molar, Third")) #2 (TITLE-ABS-KEY ("Ibuprofen")) OR (TITLE-ABS-KEY ("Anti-Inflammatory Agent*")) OR (TITLE-ABS-KEY ("Antiinflammatories")) OR (TITLE-ABS-KEY ("Anti-Inflammatory Agents, Non-Steroidal")) OR (TITLE-ABS-KEY ("Anti-Inflammatories")) OR (TITLE-ABS-KEY ("NSAIDs")) OR (TITLE-ABS-KEY ("Intravenous Ibuprofen")) OR (TITLE-ABS-KEY ("Cyclooxygenase Inhibitors")) #1 AND #2 Web of Science http://apps.webof knowledge.com/ #1 TS=("Tooth Extraction*") OR TS=("Extraction, Tooth") OR TS=("Extractions, Tooth") OR TS=("Oral Surgical Procedures") OR TS=("Surgical Procedures, Oral") OR TS=("Maxillofacial Procedure*") OR TS=("Third molar") OR TS=("Molar, Third") #2 TS=("Ibuprofen") OR TS=("Anti-Inflammatory Agent*") OR TS=("Antiinflammatories") OR TS=("Anti-Inflammatory Agents, Non-Steroidal") OR TS=("Anti-Inflammatories") OR TS=("NSAIDs") OR TS=("Intravenous Ibuprofen") OR TS=("Cyclooxygenase Inhibitors") #1 AND #2 Embase https://www.embase.com #1 ’tooth extraction’:ab,ti AND [embase]/lim OR ’oral surgery’:ab,ti AND [embase]/lim OR ’maxillofacial procedure’:ab,ti AND [embase]/lim OR ’third molar’:ab,ti AND [embase]/lim #2 ’ibuprofen’:ab,ti AND [embase]/lim OR ’antiinflammatory agent’:ab,ti AND [embase]/lim OR ‘antiinflammatories’:ab, ti AND [embase]/lim OR ’nonsteroid antiinflammatory agent’:ab,ti AND [embase]/lim OR ’anti inflammatories’:ab,ti AND [embase]/lim OR ’nsaids’:ab,ti AND [embase]/lim OR ‘intravenous ibuprofen’:ab,ti AND [embase]/lim OR ’prostaglandin synthase inhibitor’:ab,ti AND [embase]/lim #1 AND #2 LILACS http://lilacs.bvsalud. org/ #1 ("Tooth Extraction" OR "Extraction, Tooth" OR "Extractions, Tooth" OR "Tooth Extractions" OR "Oral Surgical Procedures" OR "Surgical Procedures, Oral" OR "Maxillofacial Procedure" OR "Maxillofacial Procedures" OR ‘‘Third molar’’ OR ‘‘Extração de terceiro molar’’ OR ‘‘Terceiro molar’’ OR ‘‘Extração Dentária’’ OR ‘‘Extracción Dental’’ OR ‘‘Dente Serotino’’ OR ‘‘Tercer Molar’’) #2 ("Ibuprofen" OR "Anti-Inflammatory Agents" OR "Anti Inflammatory Agents" OR "Antiinflammatories" OR "Anti-Inflammatories" OR "Non-Steroidal Anti-Inflammatory Agents" OR "NSAIDs" OR "Intravenous Ibuprofen" OR "Cyclooxygenase Inhibitors" OR ‘‘Ibuprofeno’’ OR ‘‘Anti-Inflamatórios’’ OR ‘‘Antiinflamatorios’’ OR ‘‘Anti- Inflamatórios não Esteroides’’ OR ‘‘Antiinflamatorios no Esteroideos’’) #3 (db:("BBO" OR "LILACS")) #1 AND #2 AND #3 Scielo http://www.scielo.org/ #1 (Tooth Extraction) OR (Extraction, Tooth) OR (Oral Surgical Procedures) OR (Maxillofacial Procedure) OR (Third molar) OR (Extração de terceiro molar) OR (Terceiro molar) OR (Extração Dentária) OR (Extracción Dental) OR (Dente Serotino) OR (Tercer Molar) #2 (Ibuprofen) OR (Anti-Inflammatory Agents) OR (Anti Inflammatory Agents) OR (Antiinflammatories) OR (Anti-Inflammatories) OR (Non-Steroidal Anti-Inflammatory Agents) OR (NSAIDs) OR (Intravenous Ibuprofen) OR (Cyclooxygenase Inhibitors) OR (Ibuprofeno) OR (Anti-Inflamatórios) OR (Antiinflamatorios) OR (Anti-Inflamatórios não Esteroides) OR (Antiinflamatorios no Esteroideos) #1 AND #2 Cochrane Library http://www.cochrane library.com/ #1 MeSH descriptor: [Tooth Extraction] this term only #2 MeSH descriptor: [Oral Surgical Procedures] this term only #3 MeSH descriptor: [Molar, Third] explode all trees #4 ("third molar"):ti,ab,kw #5 (Maxillofacial Procedure):ti,ab,kw #6 #1 OR #2 OR #3 OR #4 OR #5 #7 MeSH descriptor: [Ibuprofen] explode all trees #8 MeSH descriptor: [Anti-Inflammatory Agents] explode all trees #9 MeSH descriptor: [Anti-Inflammatory Agents, Non-Steroidal] this term only #10 MeSH descriptor: [Cyclooxygenase Inhibitors] this term only #11 ("Intravenous Ibuprofen"):ti,ab,kw #12 #7 OR #8 OR #9 OR #10 OR #11 #6 AND #12 OpenGrey http://www.opengrey.eu/ (‘‘Tooth Extraction’’ OR ‘‘Oral Surgical Procedures’’ OR ‘‘Maxillofacial Procedure’’ OR ‘‘Ibuprofen’’) OpenThesis http://www.o penthesis.org/ ("Tooth Extraction" OR "Oral Surgical Procedures" OR "Maxillofacial Procedure") AND ("Ibuprofen" OR "Anti Inflammatory Agents") MeSH, Medical Subject Headings. 3 CLINICS 2021;76:e2780 Intravenous ibuprofen to reduce pain Silva PUJ et al. http://www.ncbi.nlm.nih.gov/pubmed http://www.ncbi.nlm.nih.gov/pubmed http://www.scopus.com/ http://www.scopus.com/ http://apps.webofknowledge.com/ http://apps.webofknowledge.com/ https://www.embase.com http://lilacs.bvsalud.org/ http://lilacs.bvsalud.org/ http://www.scielo.org/ http://www.cochranelibrary.com/ http://www.cochranelibrary.com/ http://www.opengrey.eu/ http://www.openthesis.org/ http://www.openthesis.org/ ’ RESULTS Study selection During the first phase of the study selection, 3,257 results were found distributed in nine electronic databases, includ- ing the ‘‘grey literature.’’ After removing duplicates, 1,987 articles were retained for the analysis of titles and abstracts. After reading the titles and abstracts, five studies evaluated the full texts. After a full reading, two studies were elimi- nated for the following reasons: one study proposed to assess the presence of trismus and edema without pain assessment using the VAS (18); however, the study by Viswanath et al. (17) did not have a placebo group. The references of the three potentially eligible studies were carefully evaluated, adding up to a total of 79 articles. No additional articles were selected, resulting in three studies for the qualitative analysis. Figure 1 illustrates the search, identification, inclusion, and exclusion process of the articles. Characteristics of eligible studies The studies were published in 2019 and conducted in Turkey (7,24,25). All studies (7,24,25) respected the ethical criteria for the development of the recommended research in the country of origin, applying a consent term for all volunteers participat- ing in the study. Only two studies (7,24) used CONSORT as a methodological guideline, and two studies (24,25) provided the clinical trial registration number. A total of 150 treated patients were included, with 75 treated using IV ibuprofen and 75 in the control group. The age of the patients in each study ranged from 18 to 35 years. All studies (7,24,25) used the VAS to assess postoperative pain. Degirmenci and Yalcin (24) referred to the classification of Pell and Gregory (21) as II-B. Demirbas et al. (7) referred to surgical extraction of the lower third molar with bone impaction, following the Winter classification (horizontal or mesioangular position) (22). Küpeli and Gülnahar (25) referred to third-angled or horizontal molars. Three studies (7,24,25) were performed on third molars with a similar challenge. The three studies cited the anesthetic solutions used to induce local anesthesia. Two studies used articaine as an anesthetic salt (7,24) differing in the concentrations of vasoconstrictors of 1:100,000 and 1:200,000 epinephrine. Küpeli and Gülnahar (25) used lidocaine associated with 1:100,000 epinephrine. Figure 1 - Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 flow diagram. 4 Intravenous ibuprofen to reduce pain Silva PUJ et al. CLINICS 2021;76:e2780 Regarding postoperative medications, in the study by Degirmenci and Yalcin (24), all participants received anti- biotic therapy (amoxicillin-clavulanate 875/125 or 300 mg of clindamycin)+paracetamol 500 mg. In the study by Demir- bas et al. (7), participants received acetaminophen 500 mg (paracetamol) as a rescue medication. The study by Küpeli and Gülnahar (25) used an infusion of dexketoprofen+methyl- prednisolone+sultamicillin tosylate. Only two studies men- tioned the use of analgesics in the postoperative period (7,24). Only one study recorded mean arterial pressure and heart rate in the preoperative period (25). More details on the characteristics of the studies are shown in Table 2. Risk of bias Two eligible studies had a ‘‘low’’ risk of bias (24,25), while one study had a ‘‘moderate risk’’ (7). Table 3 shows detailed information on the risk of individual bias in the included studies (23). Item 1 was marked as ‘‘unclear’’ in a study as the randomization method was not described (25). Item 2 was marked as ‘‘unclear’’ in another study as it was not clear whether the allocation of treatment groups was hidden (7). Item 5 was marked as ‘‘unclear’’ in a study as it was not clear whether the person administering the treatment was blind to the treatment assignment (7). Item 6 was marked as ‘‘unclear’’ in two studies as the randomization blinding method was not explicit (7,24). Item 9 was marked as ‘‘not applicable’’ in one study, as there were no losses, and the entire sample was analyzed (24). Item 9, in the study by Küpeli and Gülnahar (25), was marked as ‘‘unclear.’’ Item 13 was marked as ‘‘unclear’’ in two studies, which showed disper- sion and loss between the groups; however, the study design did not mention this fact (7,25). Individual study results Degirmenci and Yalcin (24) assessed postoperative pain at 1h/1h in the first 12h and followed up until the sixth postoperative day. Demirbas et al. (7) assessed postoperative pain in the first 24h after surgery. Küpeli and Gulnahar (25) recorded pain in the first 25 min, at the end of the surgery, and in the first 48h after surgery. All studies used pain analysis methods using VAS. To facilitate pain assessment over time, it was systematically summarized in three periods: day 0 (up to 24h immediately after surgery), day 1 (24–48h after surgery), and day 2 (48–72h after surgery). Degirmenci and Yalcin (24) assessed the average postoperative pain for the first 72h after the procedure. However, Demirbas et al. (7) assessed only the values of the first 24h, and Küpeli and Gülnahar (25) did not express the numerical averages in the text. In the study by Degirmenci and Yalcin (24), the authors found no difference between the variables of pain, analgesic consumption, and the first rescue of the analgesic between IV ibuprofen and IV placebo after 72h. In the study by Demirbas et al. (7), the pain record was statistically higher in the IV placebo group than in the preoperative IV ibuprofen group, and analgesic consumption was higher in the placebo group in the first 24h. In the study by Küpeli and Gülnahar (25), pain scores were significantly higher in the placebo group than in the preemptive IV ibuprofen group 1–4h postoperatively; however, without statistical difference after 48h. Küpeli and Gülnahar (25) did not record analgesic consumption. Other results common to two or more studies are shown in Table 4. ’ DISCUSSION Several medications have been used and tested as preemptive medications, such as steroidal anti-inflammatory drugs (26,27), NSAIDs (3), and opioids (28). The use of NSAIDs in preemptive analgesia aims to prevent the release of neurotransmitters and inflammatory mediators (29). Oral ibuprofen is among the most commonly used NSAIDs for preemptive analgesia in the third molars (14). The IV form of ibuprofen was approved for the management of mild and moderate to severe pain in adults as an adjunct to opioid analgesics (30). Studies with IV ibuprofen support its effici- ency in the treatment of various types of pain of surgical and non-surgical origin (31) and the reduction of postoperative pain in the third molars, as shown in the eligible studies in the present review (7,24,25). In the extraction of third molars, the location of the tooth, depth of impaction, angulation, and root morphology are associated with the degree of surgical difficulty (32). The occurrence of pain, trismus, and edema in the postoperative period of third molar surgery is associated with age, sex, body mass, time of surgery, and tissue trauma, such as odon- tosection and osteotomy (33). Additionally, the soft tissue plays an important role in postoperative pain. A study by Patel et al. (34) on different types of flaps in the postoperative pain of third molar surgery concluded that pain was not generated due to the incision itself; however, due to the release of mediators, such as bradykinin, serotonin, and prostaglandins. In the eligible studies (7,24), patients whose surgery duration exceeded 30 and 40 min were excluded from the study. Küpeli and Gülnahar (25) did not refer to the surgical time. The absence of surgical time is a selection bias that must be considered. The extraction of the lower third molar is considered a good clinical model for assessing preemptive analgesia (3,35). After the extraction of the third molar, inflammatory mediators, such as prostaglandins, bradykinin, histamine, and leukotriene are released (36,37). Ibuprofen inhibits COX- 1 and COX-2, leading to inhibition of prostaglandin synthesis by decreasing the conversion of arachidonic acid (30). A clinical study conducted on gingival tissue during the extraction of lower third molars using a preemptive dose of 400 mg ibuprofen, observed the expression of COX-1 and COX-2 genes in the placebo group, and there was a reduction of COX-2 in the ibuprofen group (38). IV ibuprofen is a non- selective inhibitor of COX-1 and COX-2 (39). The level of postoperative pain was assessed in previous studies (7,24,25) using the VAS. This scale is a simple method used to assess the variations in pain intensity (40). Studies show that the VAS is a highly reliable instrument for measuring acute pain (41). Pain is subjective and may vary according to sex, age, and previous painful experiences (42). In the study by Degirmenci and Yalcin (24), the authors found no difference in pain scores assessed by the VAS between IV ibuprofen and IV placebo. Demirbas et al. (7) reported higher pain in the IV placebo group than that in the preoperative IV ibuprofen group. This result agrees with the study by Küpeli and Gülnahar (25), who concluded that preemptive IV ibuprofen proved to be efficient even alone. The plasma concentration of IV ibuprofen is twice as high as oral ibuprofen, reaching a maximum concentration in 0.11h, while oral ibuprofen reached a maximum in 1.5h (43). Bergese et al. (31) evaluated pain by different etiologies, n which patients received 800 mg of IV ibuprofen every 5 CLINICS 2021;76:e2780 Intravenous ibuprofen to reduce pain Silva PUJ et al. Ta b le 2 - Su m m a ry o f th e m a in ch a ra ct e ri st ic s o f th e e li g ib le st u d ie s. A u th o r, y e a r A g e (y e a rs ) To ta l n u m b e r o f p a ti e n ts S e x G ro u p s T im e o f m e d ic a ti o n a d m in is tr a ti o n P o st o p e ra ti v e m e d ic a ti o n E x cl u d e d p a ti e n ts C o m p li ca ti o n s P a ti e n ts w h o d id n o t re tu rn D e g ir m e n ci , a n d Y a lc in (2 4 ) 1 8 –2 4 4 0 G ro u p 1 M : 6 F: 1 4 G ro u p 2 M : 4 F: 1 6 G ro u p 1 : o ra l p la ce b o + in tr a ve n o u s p la ce b o G ro u p 2 : o ra l p la ce b o + in tr a ve n o u s ib u p ro fe n 4 0 0 m g 6 0 m in b e fo re a n d in fu si o n 3 0 m in b e fo re G ro u p 1 : p a ra ce ta m o l 5 0 0 m g e ve ry 8 h fo r 6 d a ys G ro u p 2 : p a ra ce ta m o l 5 0 0 m g e ve ry 8 h fo r 6 d a ys G 1 : 2 G 2 : 2 G 1 : 2 G 2 : 1 G 1 : -- G 2 : -- D e m ir b a s e t a l. (7 ) M e a n : 2 5 .1 5 0 -- G ro u p 1 : 8 0 0 m g o f in tr a ve n o u s ib u p ro fe n 6 0 m in b e fo re su rg e ry a n d in tr a ve n o u s p la ce b o (1 0 0 m L o f sa li n e ) 6 0 m in a ft e r su rg e ry G ro u p 3 : in tr a ve n o u s p la ce b o (1 0 0 m L o f sa li n e ) 6 0 m in b e fo re a n d a ft e r su rg e ry 6 0 m in b e fo re su rg e ry A ce ta m in o p h e n 5 0 0 m g G 1 : 0 G 3 : 0 G 1 : -- G 3 : -- G 1 : 0 G 3 : 0 K ü p e li a n d G ü ln a h a r (2 5 ) 2 0 –3 5 4 0 G ro u p 2 M : 8 F: 1 2 G ro u p 3 M :8 F: 1 2 G ro u p 2 : p re o p e ra ti ve in tr a ve n o u s in fu si o n in cl u d in g Ib u p ro fe n 8 0 0 m g fo r 3 0 m in G ro u p 3 : p re o p e ra ti ve in tr a ve n o u s in fu si o n o f p la ce b o (n o rm a l sa li n e ) fo r 3 0 m in 1 5 m in b e fo re su rg e ry In fu si o n o f d e xk e to p ro fe n + m e th yl p re d n is o lo n e (P re d n o l- L; M u st a fa N e vz a t, Is ta n b u l, Tu rk e y) 4 0 m g + su lt a m ic il li n su lf a te (A m p is id ; M u st a fa N e vz a t) in 1 5 0 m L o f n o rm a l sa li n e G 2 : -- G 3 : -- G 2 : -- G 3 : -- G 2 : -- G 3 : -- M , m a le ; F, fe m a le ; G 1 , g ro u p 1 ; G 2 , g ro u p 2 ; G 3 , g ro u p 3 ; -- , n o t m e n ti o n e d in th e m a n u sc ri p t; P a ra ce ta m o l = A ce ta m in o p h e n . 6 Intravenous ibuprofen to reduce pain Silva PUJ et al. CLINICS 2021;76:e2780 six hours, and a decrease in VAS scores was observed in the six hours following the medication. The pharmacokinetic profile of IV ibuprofen 800 mg (infusion for 30 min), 400 mg (infusion for 5 to 10 min), and ibuprofen 400 mg (oral) showed that the oral dose could not reach the maximum plasma concentration level of any IV dose (44). Oral admini- stration shows bioavailability, which is usually reduced by the effect of the first hepatic passage. One of the parameters for assessing the preemptive effects of medications is the consumption of supplementary post- operative analgesia and the time interval for the first analgesic (45). Degirmenci and Yalcin (24) showed a difference in analgesic consumption and the time of the first analgesic rescue between IV ibuprofen and IV placebo. Demirbas et al. (7) showed that the IV ibuprofen group, in the first hour after surgery, did not use postoperative analgesia and consumed a lower average dose in the first 24h. Küpeli and Gülnahar (25) did not mention the rescue of postoperative medications. In the present review, the preemptive effect of IV ibuprofen appeared to generally reduce acute pain and the number of postoperative episodes. Such findings were corroborated by Viswanath et al. (17), who reported that patients receiving preemptive 800 mg of IV ibuprofen in the extraction of third molars showed lower pain scores and opioid consumption than that with 1000 mg of IV acetaminophen. IV ibuprofen may have multi- modal analgesic effects when combined with a central and peripheral nerve block (46,47). In the eligible studies (7,24,25), lidocaine and articaine associated with a vasoconstrictor were used as local anes- thetics. According to Liporaci (48), local anesthesia is pre- emptive analgesia, which inhibits the sensation of pain during the first few hours after surgery. The local anesthetic used in preemptive analgesia studies can be considered a confounding factor in the results (48). In the eligible studies, the action of anesthetic salts had an intermediate duration and reduced action on analgesia. Among the limitations of this systematic review is the small number of eligible studies on the preemptive effect of IV ibuprofen on the extraction of third molars. The main reason for this is that the protocol is new. Additionally, it is an unusual route of administration on an outpatient basis. The oral route is more accepted by patients and does not require professional training. The existence of different types of preemptive protocols, heterogeneity of groups, and representation of the data did not allow a statistical analysis of the results, making it impossible to perform the meta- analysis. However, the present study is original and has the important positive point of a low risk of bias of the selected articles, which provides safer and more reliable results. The preemptive IV ibuprofen proved to be efficient in reducing pain and postoperative analgesic consumption, representing a good alternative in preemptive analgesia. Further rando- mized clinical studies should be conducted to observe the methodological quality to establish itself as a clinical protocol. ’ CONCLUSION Based on the results of the eligible studies, it is possible to suggest that the use of preemptive IV ibuprofen in the extraction of third molars reduces pain and analgesic consumption after the surgical procedure. However, clinicalTa b le 3 - R is k o f b ia s a ss e ss e d b y th e Jo a n n a B ri g g s In st it u te (J B I) C ri ti ca l A p p ra is a l To o ls fo r u se in JB I Sy st e m a ti c R e vi e w s fo r ra n d o m iz e d co n tr o ll e d tr ia l st u d ie s (2 3 ). E li g ib le a rt ic le s Q .1 Q .2 Q .3 Q .4 Q .5 Q .6 Q .7 Q .8 Q .9 Q .1 0 Q .1 1 Q .1 2 Q .1 3 % y e s/ ri sk D e g ir m e n ci a n d Y a lc in (2 4 ) O O O O O U O O -- O O O O 8 4 .6 % / lo w ri sk D e m ir b a s e t a l. (7 ) O U O O U U O O O O O O U 6 9 .2 % / m o d e ra te ri sk K ü p e li a n d G ü ln a h a r (2 5 ) U O O O O O O O U O O O U 7 6 .9 % / lo w ri sk Q .1 : W a s tr u e ra n d o m iz a ti o n u se d to a ss ig n p a rt ic ip a n ts to tr e a tm e n t g ro u p s? Q .2 : W a s th e a ll o ca ti o n to tr e a tm e n t g ro u p s co n ce a le d ? Q .3 : W e re tr e a tm e n t g ro u p s si m il a r a t b a se li n e ? Q .4 : W e re th e p a rt ic ip a n ts b li n d to th e tr e a tm e n t a ss ig n m e n t? Q .5 : W e re th o se w h o d e li ve r tr e a tm e n t b li n d to tr e a tm e n t a ss ig n m e n t? Q .6 : W e re o u tc o m e a ss e ss o rs b li n d e d to tr e a tm e n t a ss ig n m e n t? Q .7 : W e re tr e a tm e n t g ro u p s tr e a te d id e n ti ca ll y o th e r th a n th e in te rv e n ti o n o f in te re st ? Q .8 : W a s fo ll o w -u p co m p le te , a n d if n o t, w e re d if fe re n ce s b e tw e e n g ro u p s in te rm s o f th e ir fo ll o w -u p a d e q u a te ly d e sc ri b e d a n d a n a ly ze d ? Q .9 : W e re th e p a rt ic ip a n ts a n a ly ze d in th e g ro u p s to w h ic h th e y w e re ra n d o m iz e d ? Q .1 0 : W e re th e o u tc o m e s m e a su re d e q u a ll y fo r th e tr e a tm e n t g ro u p s? Q .1 1 : W e re th e o u tc o m e s m e a su re d re li a b ly ? Q .1 2 : W a s a p p ro p ri a te st a ti st ic a l a n a ly si s u se d ? Q .1 3 : W a s th e tr ia l d e si g n a p p ro p ri a te a n d a n y d e vi a ti o n s fr o m th e st a n d a rd ra n d o m iz e d co n tr o ll e d tr ia ls d e si g n (i n d iv id u a l ra n d o m iz a ti o n , p a ra ll e l g ro u p s) a cc o u n te d fo r in th e p e rf o rm a n ce a n d a n a ly si s o f th e tr ia l? / O , Y e s; -- , N o ; U , U n ce rt a in ; N /A , N o t a p p li ca b le . 7 CLINICS 2021;76:e2780 Intravenous ibuprofen to reduce pain Silva PUJ et al. studies should be encouraged to provide more scientific evidence on this subject. ’ ACKNOWLEDGMENTS This study was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior –Brazil (CAPES) – Finance code 001, and the National Council for Scientific and Technological Development (CNPq; Awards numbers: 307808/2018-1). ’ AUTHOR CONTRIBUTIONS Silva PUJ, Meneses-Santos D and Silva RP had complete roles in the identification, manuscript review, data extraction, quality assessment, analysis, manuscript drafting and revision. Silva RP conceived the idea. Vieira WA, Ramacciato JC, Silva MCP, Rode SM and Paranhos LR played major roles in the analysis, manuscript drafting and revision. All authors have read and approved the final version of the manuscript for publication. All authors agreed to be equally accountable for all aspects of this study. ’ REFERENCES 1. Jerjes W, El-Maaytah M, Swinson B, Banu B, Upile T, D’Sa S, et al. Experience versus complication rate in third molar surgery. Head Face Med. 2006;2:14. https://doi.org/10.1186/1746-160X-2-14 2. Favarini VT, Lima CAA, da Silva RA, Sato FRL. Is dipyrone effective as a preemptive analgesic in third molar surgery? A pilot study. Oral Max- illofac Surg. 2018;22(1):71-5. https://doi.org/10.1007/s10006-018-0669-y 3. Mony D, Kulkarni D, Shetty L. Comparative Evaluation of Preemptive Analgesic Effect of Injected Intramuscular Diclofenac and Ketorolac after Third Molar Surgery- A Randomized Controlled Trial. J Clin Diagn Res. 2016;10(6):ZC102-6. https://doi.org/10.7860/JCDR/2016/17696.8045 4. Paiva-Oliveira JG, Bastos PR, Cury Pontes ER, da Silva JC, Delgado JA, Oshiro-Filho NT. Comparison of the anti-inflammatory effect of dexa- methasone and ketorolac in the extractions of third molars. Oral Maxillofac Surg. 2016;20(2):123-33. https://doi.org/10.1007/s10006-015-0533-2 5. Costa FW, Esses DF, de Barros Silva PG, Carvalho FS, Sá CDL, Albuquerque AF, et al. Does the Preemptive Use of Oral Nonsteroidal Anti-inflammatory Drugs Reduce Postoperative Pain in Surgical Removal of Third Molars? A Meta-analysis of Randomized Clinical Trials. Anesth Prog. 2015;62(2):57-63. https://doi.org/10.2344/0003-3006-62.2.57 6. Kissin I. Preemptive analgesia. Anesthesiology. 2000;93(4):1138-43. https:// doi.org/10.1097/00000542-200010000-00040 7. Demirbas AE, Karakaya M, Bilge S, Canpolat DG, Kütük N, Alkan A. Does Single-Dose Preemptive Intravenous Ibuprofen Reduce Post- operative Pain After Third Molar Surgery? A Prospective, Randomized, Double-Blind Clinical Study. J Oral Maxillofac Surg. 2019;77(10):1990-7. https://doi.org/10.1016/j.joms.2019.04.019 8. Zor ZF, Isik B, Cetiner S. Efficacy of preemptive lornoxicam on post- operative analgesia after surgical removal of mandibular third molars. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(1):27-31. https:// doi.org/10.1016/j.oooo.2013.08.027 9. Gutta R, Koehn CR, James LE. Does ketorolac have a preemptive analgesic effect? A randomized, double-blind, control study. J Oral Maxillofac Surg. 2013;71(12):2029-34. https://doi.org/10.1016/j.joms. 2013.06.220 10. Chen L, Yang G, Grosser T. Prostanoids and inflammatory pain. Pros- taglandins Other Lipid Mediat. 2013;104–105:58-66. https://doi.org/ 10.1016/j.prostaglandins.2012.08.006 11. Janarthanan K, Adalarasan S. Cox-2 inhibitors in mandibular third molar surgery. J Med Life. 2019;12(2):150-5. https://doi.org/10.25122/jml-2019- 0007 12. Brignardello-Petersen R. Preemptive submucosal diclofenac may reduce postoperative pain up to 6 hours after surgical mandibular third-molar extraction but may increase adverse effects. J Am Dent Assoc. 2018;149(6): e92. https://doi.org/10.1016/j.adaj.2018.01.016 13. Velásquez GC, Santa Cruz LA, Espinoza MA. Ketoprofen is more effective than diclofenac after oral surgery when used as a preemptive analgesic: a pilot study. J Oral Facial Pain Headache. 2014;28(2):153-8. https://doi. org/10.11607/ofph.1200 14. Bauer HC, Duarte FL, Horliana AC, Tortamano IP, Perez FE, Simone JL, et al. 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. 2013;17(3):165-71. https://doi.org/10.1007/s10006-012-0360-7 15. Lau SL, Chow RL, Yeung RW, Samman N. Pre-emptive ibuprofen argi- nate in third molar surgery: a double-blind randomized controlled crossover clinical trial. Aust Dent J. 2009;54(4):355-60. https://doi.org/ 10.1111/j.1834-7819.2009.01162.x 16. Theken KN, Hersh EV, Lahens NF, Lee HM, Li X, Granquist EJ, et al. Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain. Clin Pharmacol Ther. 2019;106(3):632-41. https://doi.org/10.1002/cpt.1446 17. Viswanath A, Oreadi D, Finkelman M, Klein G, Papageorge M. Does Pre-Emptive Administration of Intravenous Ibuprofen (Caldolor) or Intravenous Acetaminophen (Ofirmev) Reduce Postoperative Pain and Subsequent Narcotic Consumption After Third Molar Surgery? J Oral Maxillofac Surg. 2019;77(2):262-70. https://doi.org/10.1016/j.joms.2018. 09.010 18. Gülnahar Y, Kupeli I. Effect of preemptive intravenous ibuprofen on postoperative edema and trismus in third molar tooth extraction: A ran- domized controlled study. J Dent Anesth Pain Med. 2018;18(3):161-7. https://doi.org/10.17245/jdapm.2018.18.3.161 19. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https://doi. org/10.1186/2046-4053-4-1 20. Aromataris E, Munn Z. Joanna Briggs Institute Reviewer‘s Manual. Adelaide: Joanna Briggs Institute. 2017. [cited June 16th, 2020]. Available from: https://reviewersmanual.joannabriggs.org/ 21. Pell GJ, Gregory GT. Impacted mandibular third molars: classification and modified technique for removal. Dent Dig. 1933;39(9):330-8. 22. Winter GB. Principles of exodontia as applied to the impacted mandibular third molar: a complete treatise on the operative technic with clinical diagnoses and radiographic interpretations. St. Louis, Mo: American medical book company; 1926. vii, 835 p. 23. Tufanaru C, Munn Z, Aromataris EC, Campbell J, Hopp L. Chapter 3: Systematic Reviews of Effectiveness. Inbook: JBI Reviewers’s Manual. 2019. Table 4 - Summary of the main qualitative/quantitative characteristics of the eligible studies. Author, year Lost to follow-up Total number of patients Pain assessment: mean Postoperative analgesic consumption (time to the first rescue) ConclusionDay (24h) Day (48h) Day (72h) Degirmenci and Yalcin (24) G 1: 2 G 2: 0 G 1: 20 G 2: 20 G1:36.75* G2:35.37* G1:37.5 G2: 30 G1:31.5 G2: 10 G1: Seven analgesics (240 min) G2: Eight analgesics (240 min) The study found no difference in the classification of pain and time to first analgesic rescue among the groups evaluated. Demirbas et al. (7) G 1: 0 G 3: 0 G 1: 25 G 3: 25 G1:14.5% G3:42.6% -- -- -- -- G1: 640 mg (in 24h) G3: 1840 mg (in 24h) Preemptive use of IV Ibuprofen decreases the experience of pain and requirement for rescue analgesia within the first 24 h after surgery. Küpeli and Gülnahar (25) G 2: 0 G 3: 0 G 2: -- G 3: -- G2: -- G3: -- -- -- -- -- G 2: -- G 3: -- Pain scores were higher in the placebo group than in the Ibuprofen group alone. G 1: group 1; G 2: group 2; G 3: group 3; IV: intravenous; * arithmetic average; --: the absolute value or average was not expressed in the manuscript. 8 Intravenous ibuprofen to reduce pain Silva PUJ et al. CLINICS 2021;76:e2780 https://doi.org/10.1186/1746-160X-2-14 https://doi.org/10.1007/s10006-018-0669-y https://doi.org/10.7860/JCDR/2016/17696.8045 https://doi.org/10.1007/s10006-015-0533-2 https://doi.org/10.2344/0003-3006-62.2.57 https://doi.org/10.1097/00000542-200010000-00040 https://doi.org/10.1097/00000542-200010000-00040 https://doi.org/10.1016/j.joms.2019.04.019 https://doi.org/10.1016/j.oooo.2013.08.027 https://doi.org/10.1016/j.oooo.2013.08.027 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/j.prostaglandins.2012.08.006 https://doi.org/10.1016/j.prostaglandins.2012.08.006 https://doi.org/10.25122/jml-2019-0007 https://doi.org/10.25122/jml-2019-0007 https://doi.org/10.1016/j.adaj.2018.01.016 https://doi.org/10.11607/ofph.1200 https://doi.org/10.11607/ofph.1200 https://doi.org/10.1007/s10006-012-0360-7 https://doi.org/10.1111/j.1834-7819.2009.01162.x https://doi.org/10.1111/j.1834-7819.2009.01162.x https://doi.org/10.1002/cpt.1446 https://doi.org/10.1016/j.joms.2018.09.010 https://doi.org/10.1016/j.joms.2018.09.010 https://doi.org/10.17245/jdapm.2018.18.3.161 https://doi.org/10.1186/2046-4053-4-1 https://doi.org/10.1186/2046-4053-4-1 https://reviewersmanual.joannabriggs.org/ 24. Degirmenci A, Yalcin E. The effect of pregabalin and ibuprofen combi- nation for pain after third molar surgery. Niger J Clin Pract. 2019; 22(4):503-10. https://doi.org/10.4103/njcp.njcp_492_18 25. Küpeli İ, Gülnahar Y. Impact of Pre-Emptive Intravenous Ibuprofen on Perioperative Analgesia in Patients Undergoing Third Molar Extraction: A Randomised Controlled Study. Turk J Anaesthesiol Reanim. 2019; 47(6):480-4. https://doi.org/10.5152/TJAR.2019.09623 26. Falci SGM, Lima TC, Martins CC, Santos CRRD, Pinheiro MLP. Preemptive Effect of Dexamethasone in Third-Molar Surgery: A Meta-Analysis. Anesth Prog. 2017;64(3):136-43. https://doi.org/10.2344/anpr-64-05-08 27. Alcântara CE, Falci SG, Oliveira-Ferreira F, Santos CR, Pinheiro ML. Pre-emptive effect of dexamethasone and methylprednisolone on pain, swelling, and trismus after third molar surgery: a split-mouth rando- mized triple-blind clinical trial. Int J Oral Maxillofac Surg. 2014;43(1):93-8. https://doi.org/10.1016/j.ijom.2013.05.016 28. Isiordia-Espinoza MA, Pozos-Guillen A, Martinez-Rider R, Perez-Urizar J. Comparison of the analgesic efficacy of oral ketorolac versus intramus- cular tramadol after third molar surgery: A parallel, double-blind, ran- domized, placebo-controlled clinical trial. Med Oral Patol Oral Cir Bucal. 2016;21(5):e637-43. https://doi.org/10.4317/medoral.21077 29. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anesth Can Anesth. 2001;48(10):1000-10. https://doi.org/10.1007/BF03016591 30. Scott LJ. Intravenous ibuprofen: in adults for pain and fever. Drugs. 2012;72(8):1099-109. https://doi.org/10.2165/11209470-000000000-00000 31. Bergese SD, Candiotti K, Ayad SS, Soghomonyan S, Gan TJ; Intravenous Ibuprofen Surveillance Trial Investigational Sites. The shortened infusion time of intravenous ibuprofen part 1: a multicenter, open-label, surveil- lance trial to evaluate safety and efficacy. Clin Ther. 2015;37(2):360-7. https://doi.org/10.1016/j.clinthera.2014.12.004 32. Akadiri OA, Obiechina AE. Assessment of difficulty in third molar surgery—a systematic review. J Oral Maxillofac Surg. 2009;67(4):771-4. https://doi.org/10.1016/j.joms.2008.08.010 33. de Santana-Santos T, de Souza-Santos aA, Martins-Filho PR, da Silva LC, de Oliveira E Silva ED, Gomes AC. Prediction of postoperative facial swelling, pain and trismus following third molar surgery based on preoperative variables. Med Oral Patol Oral Cir Bucal. 2013;18(1):e65-70. https://doi.org/10.4317/medoral.18039 34. Patel V, Managutti A, Agrawal A, Menat S, Mahida K, Patel J, et al. Comparison of the Effect of Modified Ward’s and Triangular Flap Design on Periodontium of the Second Molar after Surgical Removal of Mandibular Impacted Third Molar. Arch Clin Med Case Rep. 2020;4(3): 459-70. https://doi.org/10.26502/acmcr.96550218 35. Meechan JG, Seymour RA. The use of third molar surgery in clinical pharmacology. Br J Oral Maxillofac Surg. 1993;31(6):360-5. https://doi. org/10.1016/0266-4356(93)90191-X 36. Avelar RL, Primo BT, Vogt BF, de Oliveira e Silva ED, Antunes AA, Magalhães MT, et al. Effect of partially selective cyclooxygenase-2 inhi- bitor in the removal of third molars. J Craniofac Surg. 2012;23(2):e108-12. https://doi.org/10.1097/SCS.0b013e318231e1d5 37. Isola G, Alibrandi A, Pedullà E, Grassia V, Ferlito S, Perillo L, et al. Analysis of the Effectiveness of Lornoxicam and Flurbiprofen on Management of Pain and Sequelae Following Third Molar Surgery: A Randomized, Controlled, Clinical Trial. J Clin Med. 2019;8(3):325. https://doi.org/10.3390/jcm8030325 38. Medeiros-Albuquerque AF, Roriz-Fonteles CS, do Nascimento-Costa JJ, Viana-Silva JR, de Barros-Silva PG, Studart-Soares EC, et al. RT-qPCR study of COX-1 and -2 genes in oral surgical model comparing single-dose preemptive ibuprofen and etoricoxib: A randomized clinical trialy. J Clin Exp Dent. 2020;12(4):e371-e380. https://doi.org/10.4317/ jced.56447 39. Southworth SR, Woodward EJ, Peng A, Rock AD. An integrated safety analysis of intravenous ibuprofen (Caldolor(s)) in adults. J Pain Res. 2015;8:753-65. https://doi.org/10.2147/JPR.S93547 40. DeLoach LJ, Higgins MS, Caplan AB, Stiff JL. The visual analog scale in the immediate postoperative period: intrasubject variability and correla- tion with a numeric scale. Anesth Analg. 1998;86(1):102-6. 41. Bijur PE, Silver W, Gallagher EJ. Reliability of the visual analog scale for measurement of acute pain. Acad Emerg Med. 2001;8(12):1153-7. https://doi.org/10.1111/j.1553-2712.2001.tb01132.x 42. Fillingim RB, Maixner W. Gender differences in the responses to noxious stimuli. Pain Forum. 1995;4(4):209-21. https://doi.org/10.1016/S1082- 3174(11)80022-X 43. Pavliv L, Voss B, Rock A. Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults. Am J Health Syst Pharm. 2011;68(1):47-51. https://doi.org/10.2146/ajhp100120 44. Smith HS, Voss B. Pharmacokinetics of intravenous ibuprofen: implica- tions of time of infusion in the treatment of pain and fever. Drugs. 2012; 72(3):327-37. https://doi.org/10.2165/11599230-000000000-00000 45. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg. 2005;100(3):757-73. https://doi.org/10.1213/01.ANE.000 0144428.98767.0E 46. Kroll PB. Intravenous ibuprofen for postoperative pain. Pain Manag. 2012;2(1):47-54. https://doi.org/10.2217/pmt.11.68 47. Au AH, Choi SW, Cheung CW, Leung YY. The Efficacy and Clinical Safety of Various Analgesic Combinations for Post-Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(6):e0127611. https://doi.org/10.1371/journal.pone.0127611 48. Liporaci Junior JL. Assessment of preemptive analgesia efficacy in sur- gical extraction of third molars. Rev Bras Anestesiol. 2012;62(4):502-10. https://doi.org/10.1016/S0034-7094(12)70148-4 9 CLINICS 2021;76:e2780 Intravenous ibuprofen to reduce pain Silva PUJ et al. https://doi.org/10.4103/njcp.njcp_492_18 https://doi.org/10.5152/TJAR.2019.09623 https://doi.org/10.2344/anpr-64-05-08 https://doi.org/10.1016/j.ijom.2013.05.016 https://doi.org/10.4317/medoral.21077 https://doi.org/10.1007/BF03016591 https://doi.org/10.2165/11209470-000000000-00000 https://doi.org/10.1016/j.clinthera.2014.12.004 https://doi.org/10.1016/j.joms.2008.08.010 https://doi.org/10.4317/medoral.18039 https://doi.org/10.26502/acmcr.96550218 https://doi.org/10.1016/0266-4356(93)90191-X https://doi.org/10.1016/0266-4356(93)90191-X https://doi.org/10.1097/SCS.0b013e318231e1d5 https://doi.org/10.3390/jcm8030325 https://doi.org/10.4317/jced.56447 https://doi.org/10.4317/jced.56447 https://doi.org/10.2147/JPR.S93547 https://doi.org/10.1111/j.1553-2712.2001.tb01132.x https://doi.org/10.1016/S1082-3174(11)80022-X https://doi.org/10.1016/S1082-3174(11)80022-X https://doi.org/10.2146/ajhp100120 https://doi.org/10.2165/11599230-000000000-00000 https://doi.org/10.1213/01.ANE.0000144428.98767.0E https://doi.org/10.1213/01.ANE.0000144428.98767.0E https://doi.org/10.2217/pmt.11.68 https://doi.org/10.1371/journal.pone.0127611 https://doi.org/10.1016/S0034-7094(12)70148-4 title_link INTRODUCTION METHODS Protocol and registration Study design and eligibility criteria Sources of information, search, and selection of studies Data collection Risk of individual study bias Summary measures and summary of results Table Table 1. Strategies for database search RESULTS Study selection Characteristics of eligible studies Preferred Reporting Items for Systematic Review and MetahyphenAnalysis lparPRISMArpar 2020 flow diagram Risk of bias Individual study results DISCUSSION Table Table 2. Summary of the main characteristics of the eligible studies CONCLUSION Table Table 3. Risk of bias assessed by the Joanna Briggs Institute lparJBIrpar Critical Appraisal Tools for use in JBI Systematic Reviews for randomized controlled trial studies 23 ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS REFERENCES REFERENCES Table Table 4. Summary of the main qualitativesolquantitative characteristics of the eligible studies