1 Volume 22 2023 e238329 Original Article Braz J Oral Sci. 2023;22:e238329http://dx.doi.org/10.20396/bjos.v22i00.8668329 1 Department Conservative Dentistry, Federal University of Rio Grande do Sul, School of Dentistry, Porto Alegre, Rio Grande do Sul, Brazil. 2 Department of Production and Control of Medicines, Federal University of Rio Grande do Sul, School of Pharmacy, Porto Alegre, Rio Grande do Sul, Brazil. Corresponding author: Patricia Weidlich Ramiro Barcelos, 2492, Santa Cecília, Porto Alegre, Rio Grande do Sul, Brazil. Telephone: +55 51 99288 7959, e-mail: patricia.weidlich@ufrgs.br Editor: Dr. Altair A. Del Bel Cury Received: February 6, 2022 Accepted: October 19, 2022 Fixed and on-demand regimens of acetaminophen in periodontal surgery: randomized clinical trial Carla Cioato Piardi1 , Cristiane Galli Vaz1 , Maria Beatriz Cardoso Ferreira1 , Diogo Pilger2 , Marilene Issa Fernandes1 , Patrícia Weidlich1,* Aim: to evaluate the clinical efficacy of an acetaminophen analgesic by comparing its prescription in fixed versus on- demand schedules after periodontal surgery. The hypothesis of the study was that the fixed regimen would be more effective than the on-demand regimen for postoperative analgesics following periodontal surgery. Methods: An open randomized clinical trial was conducted. The 68 patients who needed total flap surgery to restore supracrestal tissue attachment or surgical treatment of periodontitis were randomized”. Visual Analogue Scale was used to assess pain. The fixed group (n = 34) received 500 mg of acetaminophen every 4 hours for 2 days. The on-demand group (n = 34) was instructed to use the acetaminophen “as needed,” at intervals of no less than 4 hours between doses. Ibuprofen was the rescue medication for both groups. Pain scores and medication use were recorded 2, 6, 12, 24 and 48 hours after the surgical procedure. The study was registered at the Brazilian Registry of Clinical Trials under RBR-7wv259. Results: The two groups did not differ in relation to the frequency or the intensity of pain in a 48-hour period (n=20 in the fixed group, and n=22 in the on-demand group), or even in the intention-to-treat (n=34 in each group). Individuals who experienced moderate to severe pain used rescue medication more frequently in both groups. No adverse events were reported. Conclusion: Both regimens were effective in controlling postoperative pain after periodontal surgery. Keywords: Pain, postoperative. Randomized controlled trials as topic. Periodontal diseases. Acetaminophen. https://orcid.org/0000-0001-6040-8153 https://orcid.org/0000-0001-6219-5630 https://orcid.org/0000-0002-6814-6773 https://orcid.org/0000-0002-8171-2688 https://orcid.org/0000-0003-2358-3758 https://orcid.org/0000-0003-2013-8229 2 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Introduction Surgical procedures are routine in a periodontal clinic1, and the most commonly per- formed surgeries involve total flaps2, either for surgical treatment of periodontitis, or for the reestablishment of supracrestal attached tissues. The intensity of postopera- tive pain in periodontal surgery varies greatly, and the prevalence of patients who do not need postoperative analgesic medication is not consistent in the literature. In a cross-sectional study that included different types of periodontal surgery, 32% of the patients did not use postoperative analgesics3. In another study, 20,6% of the patients undergoing periodontal surgery for different indications reported absence of postop- erative pain4. In yet another study involving periodontal surgery to treat periodonti- tis, only 8.6% of the patients reported no postoperative pain5. Different factors may interfere with the intensity of pain during the postoperative period, including anxiety6-8 and such surgical factors as surgery duration and osteotomy9. The disparity in the occurrence of postoperative pain raises doubts about the indication and prescription of analgesic drugs. The vast clinical efficacy of analgesic protocols can be seen in the literature, specif- ically in the cases that compare different medications used either alone or in com- bination to treat dental pain. A variety of studies can be found that test non-opi- oid analgesics for postoperative pain control10-12. Among these, acetaminophen is one of the most commonly used agents available on the market. Its widespread use can be attributed to its efficacy in relieving dental pain, its low incidence of adverse events12, and particularly its distinction as a first-choice medicine for preg- nant women and the elderly, or for situations when non-steroidal anti-inflammatory drugs are contraindicated13. Acetaminophen is commonly prescribed in fixed or on-demand schedules in dental clinical practice. In the latter case, it is important for the doctor to inform the maxi- mum daily dose and the minimum interval between doses, since the patients are in charge of their own pain management. The on-demand schedule has potential risks that include the use of doses beyond those recommended as the daily maximum limit. On the other hand, a fixed regimen poses the risk of a potential increase in adverse effects due to continued, higher total drug consumption. This is because the pain level at the moment of administration is not under consideration, unlike on-demand use14. Regarding the management of postoperative pain after periodontal total flap sur- gery, the literature shows variable and conflicting data that may hinder establishing an effective and safe postoperative analgesic regimen. Thus, the aim of the present study was to compare the efficacy of acetaminophen analgesics, when prescribed in a fixed or an on-demand regimen, in patients undergoing periodontal total flap surgery. The hypothesis of the present study was that the fixed regimen would be more effective than the on-demand regimen for postoperative analgesics following periodontal surgery. 3 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Materials and methods Study design and sample An open label randomized controlled trial was conducted to test the analgesic effi- cacy of acetaminophen in two different prescription schedules, according to the CONSORT statement. Although it was an open study, participants were unaware of the working hypothesis. The participants were recruited from the Periodontol- ogy Residence Clinic at the Federal University of Rio Grande do Sul (UFRGS), in Porto Alegre, Brazil. Data collection took place between May 2016 and July 2017. Adult patients who needed either total flap surgery to restablish supracrestal tis- sue attachment or surgical treatment of periodontitis were included. Patients using systemic analgesic, anxiolytic, anti-infective or anti-inflammatory agents, muscle relaxants or antidepressants were excluded, as well as those who had a previous condition of chronic or acute pain, or those who found it difficult to understand the instructions given by the research team. This study was performed according to the Declaration of Helsinki. The Research Eth- ics Committee of the Federal University of Rio Grande do Sul approved this study (CAAE 38637714.2.0000.5347). The registration at the Brazilian Registry of Clinical Trials can be found at http://www.ensaiosclinicos.gov.br/rg/RBR-7wv259/. Data collection After reading and signing the informed consent form, the participants answered questions about gender, age, years of schooling, and smoking. The Visual Ana- logue Scale (VAS)15,16 was applied to assess the basal level of pain before the beginning of the dental procedure. The following scales were applied to assess the degree of anxiety: (a) the Corah Dental Anxiety Scale (CDAS), proposed by Corah17 and validated in Brazil by Hu et al.18, and (b) the reduced version of the State-Trait Anxiety Inventory (STAI), proposed by Kaipper et al.19 and validated in Brazil by Biaggio et al.20. The CDAS comprises four questions concerning how patients feel about dental treatments. The CDAS scores range from 4 to 20, with greater scores indicating higher levels of anxiety18. The STAI scores range from 13 to 52 (state section) and 13 to 48 (trait section), with greater scores indicating higher levels of anxiety. Two previously trained researchers conducted the interview. The surgical treatments were performed by dentists from the Periodontology Residence Clinic of the School of Dentistry, UFRGS. Surgical procedures The surgeries were performed using full thickness flaps as follows: the initial inci- sion was performed parallel to the long axis of the tooth and placed approximately 1 mm from the buccal/palatal gingival margin, or intracrevicular when esthetic con- siderations were important. Buccal and palatal full‐thickness flaps were carefully elevated. Subsequently, intracrevicular incisions were made around the teeth to the alveolar crest and the third and last incision was made in a horizontal direction and in a position close to the surface of the alveolar bone crest separates the soft tissue collar of the root surfaces from the bone. The granulation tissues were removed by 4 Piardi et al. Braz J Oral Sci. 2023;22:e238329 means of manual curettes. Ostoeotomy was performed to reestablish supracrestal tissues dimensions or radicular debridement took place in cases of surgical treatment of periodontitis. Local anesthesia was administered with both infiltrative and regional techniques. The duration of the surgeries was recorded. Chlorhexidine digluconate solution (0.12%) was prescribed for topical use every 12 hours for 14 days. Allocation After the surgical procedures were completed, the participants were randomly assigned to one of the two groups for postoperative pain control: (1) fixed-time or (2) on-demand analgesic regimens. Simple randomization was performed using a com- puter-generated table. Allocation was concealed using numbered opaque envelopes, which contained the code generated by the random number table, set up by an indi- vidual not involved in the study. In the fixed-time regimen group, the patients were instructed take 500 mg of acet- aminophen every 4 hours for 48 hours, as prescribed. Administration was to start 2 hours after surgery ended. The patients received a written form to record the time periods when they used the medicine. The proposed total dose of acetaminophen in this group was 3 g/day. In the on-demand regimen group, the patients were instructed to use 500 mg of acet- aminophen when they felt pain, with an interval of no less than 4 hours between two doses, during a period of 48 hours, as prescribed. They received a written form to record the time periods when they used the medicine. The total daily dose of acet- aminophen in this group could differ, up to a maximum dose of 3 g/day. Ibuprofen 600 mg was prescribed as a rescue analgesic for both groups. The patients were instructed to use it when pain persisted after 1 hour following administration of acetaminophen, with an interval of no less than 6 hours between two doses. The total daily dose of rescue analgesic could differ, up to a maximum dose of 2.4 g/day. Each participant received 16 acetaminophen tablets (500 mg each) in a non-electronic con- tainer that could be opened manually, identified by a blue label, and 6 ibuprofen tablets (600 mg each), identified by a yellow label. Pain assessment After the surgical procedure, the participants were given instructions on how to fill out a postoperative pain control form (or a “pain diary”). The pain control form was com- posed of the VAS21, and included a section to record analgesic consumption (yes/no), and time of use. For detailed information about the pain scale, see Schirmer et al.8. The patients were instructed to fill out the pain control form 2, 6, 12, 24 and 48 hours after surgery. To improve adherence, the patients received a phone call every 24 hours reminding them to fill out the postoperative pain control form. In the return visit for postoperative evaluation and suture removal, the participants were instructed to bring back the pain diary and remaining medication, to determine adherence. The number of tablets left was counted and recorded. Patients were also questioned about the occurrence of drug-related adverse events. 5 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Adherence to treatment Adherence to the randomized scheme in both regimens was based on the partici- pants’ notes in their pain diary, and the number of remaining tablets. Adherence in the fixed regimen was assumed when the participants (a) used the acetaminophen as indicated in the prescription, and (b) respected the period of 1 hour following its administration before taking the rescue medication. Forgotten doses, observed from the records in the pain diary, were considered non-adherence to treatment. The pres- ence of a high number of tablets in the acetaminophen container suggested non-use, and a lower number of tablets than estimated suggested excessive use, and was also considered as non-adherence. Adherence in the on-demand regimen was affirmed when the individual used the acetaminophen respecting intervals of no less than 4 hours between doses, and 1 hour after its administration before taking the rescue medicine, according to the pain diary. The presence of fewer acetaminophen tablets than estimated suggested excessive use, and constituted non-adherence. Sample Calculation The sample calculation considered 70% prevalence of analgesic use in the fixed scheme group, and 35% in the on-demand group3,5. A significance level of 5%, and a beta error probability of 20% were assumed. Based on these data, a sample size of 31 individuals per group was estimated. Considering a 10% attrition rate in both groups, 34 subjects were randomized to each group, totaling 68 participants. Data analysis The data were expressed as either absolute or relative frequencies, mean and standard deviation, or median and interquartile range. The continuous variable comparisons between groups were performed using the Student t-test for inde- pendent samples, or the Mann-Whitney U test. The data of categorical variables were expressed as absolute frequencies and percentages. Comparisons were made using the chi-square test. The value of the 75th percentile was considered the reference point to analyze the anx- iety levels. Participants within the 75th percentile and with higher scores were catego- rized as “high anxiety,” and those with lower scores, as “without high anxiety.” This pro- cedure was used for the “CDAS level variables,” and the “state” (32) and “trace” levels (30) of the State-Trait Anxiety Inventory (STAI) (11). For example, subjects with “high anxiety” presented values equal to or higher than the 75th percentile for each variable. VAS data were categorized as mild (VAS 1-39), moderate (VAS 40-69), or severe (VAS ≥70) pain, according to Collins et al.15 and Al-Hamdan5. Participants were dichoto- mized into those with mild pain and those with moderate to severe pain within 6 hours after surgery. A period of 6 hours was selected because it is used routinely in the lit- erature for acute postoperative pain analysis, inasmuch as it is the period of highest pain intensity for the surgical procedure in quesion22-24. The results were shown in intention-to-treat and protocol analyses. In the intention- to-treat analysis, all 68 subjects in the sample were considered. The analysis by pro- tocol included only participants categorized as adherent to the scheme proposed by 6 Piardi et al. Braz J Oral Sci. 2023;22:e238329 the study. Statistical software SPSS® for Windows, version 18.0, was used for data analysis. The individual was considered the unit of analysis, and the significance level was established at 5%. Results Regarding the study eligibility criteria, 97 individuals indicated to undergo periodontal surgery were evaluated (Figure 1). Of these, 29 were excluded either because they did not meet the criteria (n=22), or because they did not return to perform the procedure (n = 7). The remaining 68 participants who agreed to participate were included. Characteristics of the sample and the surgical procedures are described in Table 1. There was no difference between the fixed and on-demand groups in regard to the variables analyzed. Adherence to the proposed schedule was observed in 61.76% of the total sample, with no statistically significant difference between the two groups (58.8% in the fixed regimen group versus 64.7% in the on-demand regimen group, P = 0.54; chi-square test). Figure 1. Flow diagram. Enrollment Allocation Follow-up Analysis Assessed for eligibility (n = 97) Randomized (n = 68) Excluded (n = 29) • Not meeting inclusion criteria (n = 29) • Declined to participate (n = 0) • Other reasons (n = 0) Allocated in the on-demand scheme group (n = 34) • Received allocated intervention (n = 34) • Did not receive allocated intervention (n = 0) Allocated in the fixed scheme group (n = 34) • Received allocated intervention (n = 34) • Did not receive allocated intervention (n = 0) Interntion-to-treat analysis (n = 34) Analysis by protocol (n = 20) • Excluded from analysis (n = 0) Interntion-to-treat analysis (n = 34) Analysis by protocol (n = 22) • Excluded from analysis (n = 0) Lost to follow-up (n = 0) Discontinued intervention (n = 0) Lost to follow-up (n = 0) Discontinued intervention (n = 0) 7 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Table 1. Demographic and descriptive data of groups who received prescription of acetaminophen in fixed or on-demand schemes for analgesics after periodontal procedures. Variable Fixed (n = 34) On-demand (n = 34) P Age (± SD) 41.5 (± 16.15) 41.2 (± 14.31) 0.93 a Sex – n (%) 0.60 aMale 11 (32.4) 11 (32.4) Female 23 (67.6) 23 (67.6) Schooling – mean (years) (± SD) 10.5 (± 3.22) 11 (± 2.76) 0.49 a Smoking habit – n (%) Non-smoker 27 (79.4) 24 (70.6) 0.60 aSmoker 4 (11.8) 7 (20.6) Ex-smoker 3 (8.8) 3 (8.8) Reason for surgery – n (%) Reestablish supracrestal tissue attachment 29 (85.3) 31 (91.2) 0.71 a Surgical treatment of periodontitis 5 (14.7) 3 (8.8) Local anesthetic solution – n (%) Lidocaine 18 (52.9) 23 (67.6) 0.71 a Mepivacaine 11 (32.4) 8 (23.5) Prilocaine 2 (5.9) 2 (5.9) Not registered 3 (8.8) 1 (2.9) Number of local anesthetic tubes used – n (± SD) 2.72 (± 0.86) 2.49 (± 0.81) 0.26 a Removal of bone tissue – n (%) No 11 (32.4) 8 (23.5) 0.59 a Yes 23 (67.6) 26 (76.5) Duration of surgery (h & min) (mean ± SD) 1:31 (± 0:40) 1:23 (± 0:25) 0.37 a Furcation injury – n (%) Yes 4 (11.8) 2 (5.9) 0.67 a No 30 (88.2) 32 (94.1) Anxiety-Trace (IDATE) - Total scores Median (P25- P75) 26 (24.5-32.2) 27.5 (23-31.2) 0.48 b Anxiety-State (IDATE) - Total scores Median (P25- P75) 28 (24-31) 26 (24-30) 0.53 b CDAS - Total scores – Median (P25- P75) 8 (5-11.2) 8 (5-10.5) 0.29 b a Chi-square test for categorical variables, and Student t test for independent samples for continuous variables. b Mann-Whitney test. IDATE: Trait-State Anxiety Inventory. CDAS: Corah Dental Anxiety Scale. P25 e P75 (P25- P 75): interquartile range The frequency of the postoperative pain levels at 2, 6, 12, 24 and 48 hours for par- ticipants who received an analgesic prescription in a fixed or on-demand schedule is shown in Table 2. When the frequency of the pain levels was compared with each of the schemes in the different periods, no statistically significant difference was 8 Piardi et al. Braz J Oral Sci. 2023;22:e238329 observed (P>0.05 for all the time periods, using the Friedman test). The pain scores of patients who received a prescription for fixed or on-demand analgesics is shown as supplementary material (Supplementary Table 1). The frequency of participants using rescue medication at each time interval is shown in the Supplementary Table 2. There was no difference between the groups in any of the periods evaluated in the protocol analysis or the intention-to-treat analysis. Table 2. Distribution frequency of pain levels assessed at 2, 6, 12, 24 and 48 hours after periodontal procedures for the groups that received a prescription of acetaminophen in fixed or on-demand regimens, in an intention-to-treat analysis (n = 68). The VAS scores are categorized as follows: mild pain scores = from 1 to 39; moderate pain scores = from 40 to 69; severe pain scores = ≥ 70.  Pain levels Analgesic scheme 2 hours 6 hours 12 hours 24 hours 48 hours Mild Fixed 85.3% 82.4% 91.2% 97.1% 97.1% On-demand 85.3% 73.5% 79.4% 85.3% 85.3% Moderate Fixed 11.8% 14.7% 2.9% 2.9% 2.9% On-demand 5.9% 11.8% 14.7% 8.8% 8.8% Severe Fixed 2.9% 2.9% 5.9% 0% 0% On-demand 8.8% 14.7% 5.9% 5.9% 5.9% P a 0.92 0.30 0.20 0.85 0.85 a Friedman test. In Table 3, the sample was categorized into two groups according to the reported pain intensity over a period of 6 hours – participants with mild pain or those with moderate to severe pain. There were no significant differences between the two groups regard- ing sociodemographic variables related to the surgical procedure or anxiety. Patients that experienced moderate to intense pain used rescue medication more frequently than those feeling mild to moderate pain. There were no reports of adverse events related to consumption of the prescribed drugs in either group. Table 3. Distribution of individuals who presented mild pain or moderate to severe pain 6 h after periodontal procedures, according the sociodemographic and surgical characteristics, anxiety scores and prescription of acetaminophen in fixed or on-demand schemes. Variable Mild pain n=53 Moderate to severe pain n=15 P Age (years) (mean±SD) a 40.2 (±15.2) 45.0 (±15.37) 0.28 Sex – n (%) c Female 35 (66) 11 (73.3) 0.59 Male 18 (34) 4 (26.7) Continue 9 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Continuation Smoking habit – n (%) c Smoking 9 (17.0) 2 (13.3) 0.76Non-smoking 40 (75.5) 11 (73.3) Ex-smoker 4 (7.5) 2 (13.3) Duration of the surgery (h & min) (mean±SD) a 01:26 (±00:35) 01:29 (±00:26) 0.73 Osteotomy c Yes 39 (73.6) 10 (66.7) 0.59 No 14 (26.4) 05 (33.3) Anxiety-Trace (IDATE)d - Median (P25- P 75) b 27 (24-30) 26 (24-31) 0.43 Anxiety-State (IDATE)d - Median (P25- P 75) b 29 (24-32) 28 (23-31) 0.86 CDASd - Median (P25- P75) b 8 (5-11) 9 (5-12) 0.32 Acetaminophen administration scheme - n (%)c Fixed 28 (52.8) 6 (40.0) 0.38 On-demand 25 (47.2) 9 (60.0) Adherence to the scheme prescribed - (n %)c Yes 36 (67.9) 9 (60.0) 0.49 No 17 (32.1) 6 (49.0) Use of acetaminophen in the proposed period - n (%)e Yes 48 (90.6) 14 (93.3) 0.60 No 5 (9.4) 1 (6.7) Use of rescue medication - n (%)e Yes 8 (15.1) 9 (60) 0.001 No 45 (84.9) 6 (40) Dose of ibuprofen used in the proposed period (mg) - Median (P25- P75) b 0 (0/0) 600 (0/600) 0.001 a Student t test for independent samples b Mann-Whitney U test c Chi-square test d Total scores e Exact Fisher test Discussion The present clinical trial compared the analgesic efficacy of two acetaminophen pre- scription schedules—fixed-dose or on-demand—in the postoperative period of total flap periodontal surgery. Both prescribed regimens were found to be effective in reducing pain levels, and rescue medication was used more frequently by patients who experienced moderate to intense pain. Few studies have compared fixed to on-demand schedules – the latter is known as the pro-rata regimen, or “as needed” in more popular vernacular. Only two studies were found for the postoperative period of periodontal surgery. One compared the preop- 10 Piardi et al. Braz J Oral Sci. 2023;22:e238329 erative use of etodolac in a fixed regimen with acetaminophen and hydrocodone in a pro-rata regimen, and found no difference between the pain scores for the two regi- mens25. The other study compared the preoperative use of ibuprofen associated to a fixed prescription of the same drug in the postoperative period with the preoperative use of placebo associated to ibuprofen in an “as needed” regimen in the postoperative period of periodontal surgery26. There was no difference in the postoperative pain lev- els, thus corroborating the results of the present study. However, the design of these studies is not adequate enough to allow an effective comparison to be made between the prescription drug regimens. The reason there is no difference between the two analgesic regimens tested could be attributed to the fact that postoperative pain after periodontal surgery is predomi- nantly mild and moderate in intensity3; this would make the efficacy of acetaminophen suffice even when used sporadically22. In the present clinical trial, there was a predom- inance of mild pain throughout the 48 hours of observation. Pain peaks, expressed as the highest median scores on the VAS scale, were observed at the 2nd and 6th postoperative hours, in both the fixed and on-demand groups. In fact, the literature shows that pain is more intense in the first 6 to 12 hours after periodontal surgery. One clinical trial involving surgery and reestablish- ment of supracrestal attached tissues observed a reduction in pain scores after the 6th and the 8th postoperative hour23. Another study with surgical treatment of periodontitis showed higher levels of pain in 6 hours, and a reduction in pain levels between 24 and 72 hours24. It is of fundamental importance to evaluate adverse events in drug studies, with the aim of drawing a safety profile of the studied drug12. In this study, there were no reports of adverse events associated with acetaminophen or ibuprofen. However, the sample size calculation was not based on this outcome; therefore, there could be a beta error. In two systematic reviews, the adverse effects attributed to acetamino- phen (nausea, vomiting, and drowsiness) were classified as mild and transient, similar to those described by the placebo group12,22. Several additional factors have been associated with reports of higher levels of post- operative pain, including longer surgical procedures and bone tissue removal3,6,9. These variables were analyzed in our study, and no significant association with pain intensity was observed. Non-adherence to the proposed scheme was not related to pain intensity either. Our findings corroborate those of another study, which also used acetaminophen to control acute pain, and observed no association between adher- ence to fixed or on-demand protocols and pain levels27. Smoking is another condition that may also be associated with higher levels of postoperative pain. In a study on fac- tors associated with pain and analgesic consumption, smokers were 47% more likely to report pain after non-surgical scaling and root planing than nonsmokers8. However, in the present study, no association was found between smoking and higher levels of postoperative pain, in line with the findings of Beaudette6 involving the occurrence of pain following soft tissue grafting or implant surgery. It should be pointed out that only 20 to 30% of the participants in this study were smokers, which may not be enough to show a statistical difference. 11 Piardi et al. Braz J Oral Sci. 2023;22:e238329 Anxiety is also a factor that can influence pain levels28-32, but the state and trait anxiety, and the dental anxiety scores in the present study did not show any significant differ- ences between patients who reported mild pain or moderate to severe pain. It can be postulated that periodontal patients who undergo surgical procedures as part of their entire periodontal treatment are already familiar with the periodontist and dental staff, hence representing a anxiety-reducing factor. At the same time, procedures involving periodontal surgery most commonly receive mild postoperative pain scores, associ- ated with less anxiety and fear. The present study has limitations. All the efforts made in data collection focused on increasing adherence to a patient-randomized scheme. However, in addition to cases of non-adherence (35.3%), there were also cases where the information on medication use and pain control recorded on a specific form by patients may not have reflected exactly what occurred in the postoperative period. It is also important to consider that a small group of patients in both groups experienced pain 48 hours after the proce- dure. A longer follow-up period should be considered for these patients. Considering that the anesthetic used was not standardized, the pain levels reported may have been influenced by the duration of the different anesthetics. In addition, the surgeries were performed by different professionals and although they were all in the periodon- tics residency course, they could be at different stages of training and with different clinical and surgical skills. In conclusion, the present study demonstrated that the use of acetaminophen, in a fixed-dose or on-demand regimen is effective in postoperative pain control after periodontal total flap surgery. Since both regimens were effective, other parameters, such as patient safety and convenience, should be considered before prescribing either one or the other. Funding sources This study did not receive any specific grant from funding agencies in the public, com- mercial, or not-for-profit sectors. Conflict of interest None. Data availability Datasets related to this article are available upon request to the corresponding author. Author contribution C. Piardi originated and designed the study, acquired data, analyzed and interpreted data, drafted the manuscript and critically revised it; C. G. Vaz acquired and inter- preted data and critically revised the manuscript; M. B. C. Ferreira originated and designed the study, analyzed and interpreted data, and revised the manuscript for important intellectual content; D. Pilger analyzed and interpreted data, and revised the manuscript for important intellectual content M. I. Fernandes originated and designed 12 Piardi et al. Braz J Oral Sci. 2023;22:e238329 the study, analyzed and interpreted data, and revised the manuscript for important intellectual content the manuscript; P. Weidlich originated and designed the study, analyzed and interpreted data, and critically reviewed the manuscript for important intellectual content. All authors approved the final version of the document to be pub- lished. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the manuscript were appropriately investigated and resolved. Supplementary Table 1. Visual Analog Scale (VAS) scores for pain evaluated 2, 6, 12, 24 and 48 hours after periodontal procedures, in the groups that received acetamoniphen prescription in fixed or on-demand schedules, based on intention-to-treat and per protocol analysis. Data are expressed as median and interquartile range (P25- P 75). VAS 2 h VAS 6 h VAS 12 h VAS 24 h VAS 48 h Intention-to- treat analysis (n=68) Fixed (n=34) 10.5 (1.5–30.7)a 10.0 (7.5–30.0)a 3.0 (0–18.5)ac 2.0 (0–8.2)bc 1.0 (0–4.0)b On-demand (n=34) 8.5 (0.75–27.7)ac 14.0 (1.0–2.5)a 5.5 (0.75–21)ac 2.0 (0–11.2)bc 2.0 (0–10.7)bc Per protocol analysis (n=42) Fixed (n=20) 12.0 (0.5–36.2)a 10.0 (0.25-2.0)a 2.0 (0–36.0)ab 2.0 (0–10.0)b 1.0 (0–4.0)b On-demand (n=22) 6.0 (0–29.75)a 11.0 (1.0–9.5)a 5.5 (0–26.75)a 2.0 (0–10.5)a 2.0 (0–7.75)a Different letters represent intragroup differences, Friedman and Dunn’s test. Supplementary Table 2. Frequency of individuals who used rescue medication at 6, 12, 24 and 48 hours after periodontal procedures, in the groups that received acetamoniphen prescription in fixed or on-demand schemes, based on intention-to-treat and by per protocol analysis. Analysis period Frequency of use of rescue medication Intention-to-treat analysis (n=68) Per protocol analysis (n=42) Fixed group n=34 On-demand group n=34 P a Fixed group n=20 On-demand group n=22 P a 6 h 14.7% 35.3% 0.17 0% 18.2% 0.13 12 h 8.8% 29.4% 0.85 0% 13.6% 0.23 24 h 5.9% 17.6% 0.31 0% 4.5% 0.33 48 h 11.7% 20.6% 0.17 5% 9.0% 0.62 a Chi-square test, comparing fixed and on-demand groups using or not using rescue medication, in each period of time. References 1. Graziani F, Karapetra D, Mardas N, Leow N, Donos N. Surgical treatment of the residual periodontal pocket. Periodontol 2000. 2018 Feb;76(1):150-63. doi: 10.1111/prd.12156. 2. Graziani F, Karapetsa D, Alonso B, Herrera D. Nonsurgical and surgical treatment of periodontitis: how many options for one disease? Periodontol 2000. 2017 Oct;75(1):152-88. doi: 10.1111/prd.12201. 3. Curtis JW, Mclain JB, Hutchinson RA. The incidence and severity of complications and following periodontal surgery. J Periodontol. 1985 Oct;56(10):597-601. doi: 10.1902/jop.1985.56.10.597. 13 Piardi et al. Braz J Oral Sci. 2023;22:e238329 4. Mei CC, Lee FY, Yeh HC. Assessment of pain perception following periodontal and implants surgeries. J Clin Periodontol. 2016 Dec;43(12):1151-9. doi: 10.1111/jcpe.12618. 5. Al-Hamdan K. Pain perception following different periodontal procedures. Pak Oral Dent J. 2009;29(1):63-8. 6. Beaudette RJ, Fritz CP, Sullivan JP, Piccini A, Ward EW. Investigation of factors that influence pain experienced and the use of pain medication following periodontal surgery. J Clin Periodontol. 2018 May;45(5):578-85. doi: 10.1111/jcpe.12885. 7. Fardal Ø, McCulloch CA. Impact of anxiety on pain perception associated with periodontal and implant surgery in a private ractice. J Periodontol. 2012 Sep;83(9):1079-85. doi: 10.1902/jop.2011.110562. 8. Schirmer C, dos Santos GO, Rost JF, Ferreira MBC, Weidlich P. Factors associated with pain and analgesic consumption following non-surgical periodontal therapy under local anaesthesia and carried out by dental students. J Clin Periodontol. 2018 Jan;45(1):68-77. doi: 10.1111/jcpe.12833. 9. Tan WC, Krishnaswamy G, Ong MMA, Lang NP. Patient-reported outcome measures after routine periodontal and implant surgical procedures. J Clin Periodontol. 2014 Jun;41(6):618-24. doi: 10.1111/jcpe.12248. 10. Caporossi SL, Dos Santos SC, Calcia BBT, Cenci SM, Muniz GMWF, Lima SG. Pharmacological manageent of pain after periodontal suegery: a systemantic review with meta-analysis. Clin Oral Investig. 2020 Aug;24(8):2559-78. doi: 10.1007/s00784-020-03401-6. 11. Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane database Syst Rev. 2008 Oct;2008(4):CD004602. doi: 10.1002/14651858.CD004602.pub2 12. Bailey E, Worthington HV, van Wijk A, Yates JM, Coulthard P, Afzal Z. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev. 2013 Dec;(12):CD004624. doi: 10.1002/14651858.CD004624.pub2. 13. Laskarides C. Update on analgesic medication for adult and pediatric detal patients. Dent Clin North Am. 2016 Apr;60(2):347-66. doi: 10.1016/j.cden.2015.11.006. 14. Hobson A, Wiffen PJ, Conlon JA. As required versus fixed schedule analgesic administration for postoperative pain in children. Cochrane Database Syst Rev. 2015 Feb;2015(2):CD011404. doi: 10.1002/14651858.CD011404.pub2. 15. Collins SL, Moore RA, McQuay HJ. The visual analog pain intensity scale: What is moderate pain in millimeters? Pain. 1997 Aug;72(1-2):95-7. doi: 10.1016/s0304-3959(97)00005-5. 16. Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Hals EK, et al. Assessment of pain. Br J Anaesth. 2008 Jul;101(1):17-24. doi: 10.1093/bja/aen103. 17. Corah NL. Development of a Dental Anxiety Scale. J Dent Res. 1969 Jul-Aug;48(4):596. doi: 10.1177/00220345690480041801. 18. Hu L W, Gorentein C, Fuentes D. Portuguese version of Corah’s Dental anxiety Scale: Transcultural adaptation and reliability analysis. Depress Anxiety. 2007;24(7):467-71. doi: 10.1002/da.20258. 19. Kaipper MB, Chachamovich E, Hidalgo MPL, da Silva Torres IL, Caumo W. Evaluation of the structure of Brazilian State-Trait Anxiety Inventory using a Rasch psychometric approach. J Psychosom Res. 2010 Mar;68(3):223-33. doi: 10.1016/j.jpsychores.2009.09.013. 20. Biaggio AMB, Natalício L, Spielberger CD. [Development of the experimental form in Portuguese of Spielberger’s State-Trait Anxiety Inventory (STAI)]. Arq Bras Psiq. 1977;29(3):31-44. Portuguese. 21. Price DD, McGrath PA, Raffi A, Buckingham B. The validation of Visual Analogue Scales as ratio Scale Measures for chronic and experimental pain. Pain. 1983 Sep;17(1):45-56. doi: 10.1016/0304-3959(83)90126-4. 14 Piardi et al. Braz J Oral Sci. 2023;22:e238329 22. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane database Syst Rev. 2013 Jun 24;2013(6):CD010210. doi: 10.1002/14651858.CD010210.pub2. 23. Steffens JP, Santos FA, Sartori R, Pilatti GL. Preemptive dexamethasone and etoricoxib for pain and discomfort prevention after periodontal surgery: a double-masked, crossover, controlled clinical trial. J Periodontol. 2010 Aug;81(8):1153-60. doi: 10.1902/jop.2010.100059. 24. Al-Bayati O, Font K, Soldatos N, Carlson E, Parsons J, Powell C. Evaluation of the need to prescribe opioid medication to control post-surgical pain of different periodontal/oral surgeries. J Periodontol. 2021 Jul;92(7):1030-5. doi: 10.1002/JPER.20-0315. 25. Tucker PW, Smith JR, Adams DF. A comparison of 2 analgesic regimens for the control of postoperative periodontal discomfort. J Periodontol. 1996 Feb;67(2):125-9. doi: 10.1902/jop.1996.67.2.125. 26. Pearlman B, Boyatzis S, Daly C, Evans R, Gouvoussis J, Highfield J, et al. The analgesic efficacy of ibuprofen in periodontal surgery: a multicentre study. Aust Dent J. 1997 Oct;42(5):328-34. doi: 10.1111/j.1834-7819.1997.tb00139.x.. 27. Haanstra TM, Kamper SJ, Williams CM, Spriensma AS, Lin CC, Maher CG, et al. Does adherence to treatment mediate the relationship between patients’ treatment outcome expectancies and the outcomes of pain intensity and recovery from acute low back pain? Pain. 2015 Aug;156(8):1530-6. doi: 10.1097/j.pain.0000000000000198. 28. Yang MMH, Hartley RL, Leung AA, Ronksley PE, Jetté N, Casha S, et al. Preoperative predictors of poor acute postoperative pain control: a systematic review and meta-analysis. BMJ Open. 2019 Apr;9(4):e025091. doi: 10.1136/bmjopen-2018-025091. 29. Lin CS, Wu SY, Yi CA. Association between anxiety and pain in dental treatment: a systematic review and meta-analysis. J Dent Res. 2017 Feb;96(2):153-62. doi: 10.1177/0022034516678168. 30. Tickle M, Milsom K, Crawford JIF, Aggarwal RV. Predictors of pain associated with routine procedures performed in general dental pracrice. Community Dent Oral Epidemiol. 2012 Aug;40(4):343-50. doi: 10.1111/j.1600-0528.2012.00673.x. 31. Torres-Lagares D, Recio-Lora C, Castillo-Dalí G, Ruiz-de-León-Hernández G, Hita-Iglesias P, Serrera-Figallo MA, et al. Influence of state anxiety and trate anxiety postoperative in oral surgery. Med Oral Patol Oral Cir Bucal. 2014 Jul;19(4):e403-8. doi: 10.4317/medoral.19604. 32. Kim S, Lee YJ, Lee S, Moon HS, Chung MK. Assessment of pain and anxiety following surgical placement of dental implants. Int J Oral Maxillofac Implants. 2013 Mar-Apr;28(2):531-5. doi: 10.11607/jomi.2713.