This systematic review was reported according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2020) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Page et al., 2021). The study protocol was registered (CRD42022324766) on the PROSPERO platform (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=324766).

These criteria were described using the Population, Intervention, Comparison, Outcome and Study type (PICOS) framework.

Clinical trials must report at least one of the following primary outcomes: pain reduction or control and patient discomfort (for at least 8 h after the surgical procedures), swelling/edema, and trismus. Pain must be assessed using a visual analogue scale or other scale; and edema should be assessed by angles or distances between different facial landmarks; and trismus by interincisal distance.

Secondary outcomes evaluated were the occurrence of adverse drug reactions, need for clinical reintervention, and satisfaction with the treatment.

The search was conducted using Medical Subject Headings (MeSH) terms, with the strategy adapted for each database (see Supplementary Material SA).

After executing the search strategies on each database, the researchers imported the results of each search into an EndNote^® library for removal of duplicates and selection of the studies for review.

Four reviewers (LPL, CBM, EGF, and TLM), working in pairs and independently, screened potentially relevant citations and abstracts and applied the selection criteria. Full texts of all potentially eligible articles were obtained. The same reviewers confirmed the eligibility of each article by reading the full text. Disagreements were resolved by consensus and, when necessary, a third reviewer was consulted for a final decision (RHLM).

Pairs of reviewers (LPL, CBM, EGF and TLM), independently, performed the data extraction, using a Microsoft Excel form, standardized and pretexted for this step. Reviewers extracted patient data, methods, interventions and outcomes evaluated. Disagreements were resolved by consensus and, when necessary, arbitrated by a third reviewer (RHLM or LCL).

The version of the Cochrane Collaboration was used to assess risk of bias. The reviewers, in pairs and independently (LPL,CBM, EGF and TLM), assigned the risk of bias for each clinical trial according to the following criteria: sequence generation: was the allocation sequence adequately generated?; Allocation concealment: was allocation adequately concealed?; Blinding of participants and care providers for each main outcome: was the knowledge of the allocated treatment adequately prevented during the trial?; Blinding of outcome assessors for each main outcome: was the knowledge of the allocated treatment adequately prevented during the trial?; Incomplete outcome data for each main outcome: did more than 10% of participants withdraw, and were incomplete outcome data adequately addressed?; Selective outcome reporting: was there any suggestion of selective outcome reporting?; Other sources of bias: was the trial apparently free of other problems that could put it at high risk of bias?

The reviewers assigned response options of “definitely yes,” “probably yes,” “probably no,” and “definitely no” for each of the domains, with “definitely yes” and “probably yes” ultimately being assigned a low risk of bias, and “definitely no” and “probably no,” a high risk of bias (Akl et al., 2013). The reviewers settled disagreements by consensus and a third reviewer (RHLM or LCL) was consulted when necessary.

The results were summarized through narrative synthesis, since it was not possible to perform meta-analyses due to disparities among the clinical procedures, drugs and doses used. Further information regarding the methods adopted is described in the protocol registered as already mentioned.

The search strategy led to the identification of 1,866 publications. After removal of duplicates and reading of titles and abstracts, 20 studies remained for full-text screening. Based on the eligibility criteria, a total of 6 RCTs were included in the review (Figure 1). The excluded studies are listed in Supplementary Material SB.

Six RCTs included involved 250 participants undergoing periodontal surgeries. Of the individuals for whom gender was reported, 75 were women and 57 men. Gender was not reported for the remaining 118 participants. The anti-inflammatory agents assessed in the clinical trials included dexamethasone 8 mg, celecoxib 200 mg, etoricoxib 90 mg and 120 mg, and ketorolac 20 mg. Patient follow-up ranged from the first 8 h to 4 days.

Of the 250 participants, 134 underwent flap debridement, 43 mucoperiosteal flap surgery, 15 root debridement and osseous recontouring, and 58 mucogingival grafts.

The studies included were published between 2010 and 2015. Four of the RCTs were conducted in Brazil, and the other 2 in India and Italy, respectively. The studies reported no information on research funding and did not register their protocols (Table 1).

Information about the risk of bias is described in Figure 2.

The studies reported the outcomes pain (n = 6) and anxiety (n = 2). The effectiveness of ketorolac 20 mg for reducing post-operative pain was compared to placebo (Trombelli et al., 1996) (Table 2). Three clinical trials assessed the use of dexamethasone 8 mg compared to etoricoxib (90 and 120 mg) and placebo for controlling post-operative pain (Steffens et al., 2010; Zardo et al., 2013; Konuganti et al., 2015). The use of celecoxib 200 mg was compared to etoricoxib (90 and 120 mg) and placebo for post-operative pain control (Steffens et al., 2011; Steffens et al., 2012). The effectiveness of ketorolac 20 mg for reducing post-operative pain was compared to placebo (Trombelli et al., 1996).

The main findings for effectiveness reported by the clinical trials are outlined below:

The present study reviewed the available evidence on the effectiveness and safety of the use of preemptive analgesia in patients undergoing periodontal surgical procedures: open-flap debridement (Steffens et al., 2011; Steffens et al., 2012; Konuganti et al., 2015), mucoperiosteal flap (Trombelli et al., 1996), root debridement with osseous recontouring (Steffens et al., 2010) and gingival graft (Zardo et al., 2013). None of the studies reviewed met all the assessment criteria for risk of bias, where the main issues found pertained to allocation concealment and blinding of individuals involved. The most investigated drugs were dexamethasone 8 mg and etoricoxib 90 mg and 120 mg. Meta-analyses were not performed owing to the disparities in clinical procedures, drugs and doses studied.

Preemptive analgesia with dexamethasone 8 mg were more effective than placebo for controlling post-operative pain (Steffens et al., 2010; Zardo et al., 2013; Konuganti et al., 2015). Likewise, etoricoxib 90 mg or 120 mg were also superior to placebo for controlling post-operative pain (Steffens et al., 2010; Steffens et al., 2011; Steffens et al., 2012; Zardo et al., 2013; Konuganti et al., 2015). Ketorolac 20 mg was more effective than placebo for pain control (Trombelli et al., 1996).

None of the studies assessed adverse effects, precluding any conclusion on the safety of the interventions studied. Furthermore, the outcomes swelling, trismus, need for clinical reintervention and treatment satisfaction were not addressed in the clinical trials, limiting out findings about this topic on the preemptive use of analgesia in periodontal surgeries. Since stress and dental anxiety can vary among patients and potentially impact pain perception, the State-Trait Anxiety Inventory and Corah’s Dental Anxiety Scale were applied in two studies (Steffens et al., 2010; Steffens et al., 2011). However, there was no statistical difference between the patients in different groups of both studies.

Although no information was collected on the safety of using the drugs investigated by the studies, when administered as a single oral dose, these medications are likely to be safe for use. In addition, lost follow-up reported by some of the studies reviewed were for reasons unrelated to safety of the medications.

Notably, a previous systematic review assessed the effectiveness of the use of oral anti-inflammatory corticosteroids in patients undergoing third molar extraction, periodontal or implant surgeries. This review included three of the clinical trials included in our study (Wagner et al., 2022).

This review was methodologically robust, employing explicit eligibility criteria, risk of bias rating, a broad comprehensive search of databases, and independent dual review of each study included.

The primary studies included were a factor limiting the review findings, given the methodological quality of the clinical trials, different comparators and doses and failure to address relevant clinical outcomes, ultimately preventing meta-analyses.

This review provided a synthesis of the available evidence in the literature on the effectiveness of preemptive analgesia with oral use of dexamethasone 8 mg, etoricoxib (90 mg and 120 mg) and ketorolac 20 mg in periodontal surgical procedures. The findings suggest that preemptive oral use of these anti-inflammatory drugs appears to control post-operative pain and discomfort after periodontal surgical procedures. The study findings can help inform decision-making in dental practice regarding the control of post-operative pain induced by periodontal surgeries.

Considering the various limitations, further clinical trials involving more rigorous methodology and standardized methods of gathering outcome data should by conducted. These investigations could increase the reliability of findings, indicating which medications are deemed effective and safe for preemptive analgesia in periodontal surgical procedures.