Type of the Paper (Article Journal of Baghdad College of Dentistry, Vol. 34, No. 2 (2022), ISSN (P): 1817-1869, ISSN (E): 2311-5270 37 Research Article Effects of various analgesics on pain perception and rate of tooth movement: a randomized controlled clinical study Asem A M Abdaljawwad1, Dheaa H Al-Groosh2 1 Department of Orthodontics, College of Dentistry, University of Anbar, Iraq. 2 Department of Orthodontics, College of Dentistry, University of Baghdad, Iraq. * Correspondence: dheaaha73@yahoo.com Abstract: Background: Pain is one of the most reported side effects of orthodontic treat- ment despite the advanced technology in orthodontics. Many analgesics have been intro- duced to control orthodontic pain including acetaminophen and selective and nonselective nonsteroidal anti-inflammatory drugs. The great concern about these drugs is their adverse effect on rate of teeth movement. Aims: The purpose of this study was to evaluate and com- pare the effect of acetaminophen, ibuprofen and etoricoxib on pain perception and their in- fluence on the rate of teeth movement during leveling and alignment stage. Methods: Forty patients were evenly and randomly distributed in a blinded way to one of four groups: pla- cebo (starch capsules), acetaminophen 500mg thrice daily, ibuprofen 400mg thrice daily, and etoricoxib 60mg once daily. The drugs were given one hour before bonding and archwire placement and continued for three days. A visual analogue scale was used to express pain levels before and after archwire placement, on the first, second, third, and seventh day. Little’s irregularity index was measured before bonding and at every activation visit until the end of the alignment and leveling stage. Results: All three drugs showed a lower pain level than placebo at the bonding and first activation visits. Etoricoxib showed the least pain level among other drugs followed by ibuprofen. No statistically significant differences were found be- tween the drug groups and the placebo at the second and third activation visits. No statisti- cally significant differences were detected between the 4 experimental groups concerning the rate of teeth movement. Conclusions: The three drugs were only effective in controlling pain during the first two visits of orthodontic treatment; and etoricoxib 60mg/day was the best. All three drugs had no influence on rate of teeth movement when used in their least recom- mended dose. Keywords: Orthodontic pain, pain perception, etoricoxib, analgesics. Introduction Orthodontic pain was reported to be one of the most negative effects of orthodontic treatment, it has been rated as a major reason for discontinuing treatment (1-3). Previous studies have well documented that orthodontic pain begins between 4h - 12h after orthodon- tic force application, peaks after 1 day, gradually subsides 3–7 days thereafter and returns to baseline levels after 1 month (4-6). Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for the relief of orthodontic pain for decades. Their effectiveness in orthodontic pain relief has been validated, but their side effect of reducing the rate of tooth movement is still being debated (7-9), making NSAIDs not routinely used for pain control in orthodontic practice. Received date: 12-12-2021 Accepted date: 20-1-2022 Published date: 15-6-2022 Copyright: © 2022 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Com- mons Attribution (CC BY) license (https://creativecommons.org/li- censes/by/4.0/). https://doi.org/10.26477/jbc d.v34i2.3144 mailto:dheaaha73@yahoo.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://doi.org/10.26477/jbcd.v34i2.3144 https://doi.org/10.26477/jbcd.v34i2.3144 J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 38 Traditional NSAID are nonselective for two isoforms of cyclooxygenase (COX), COX-1 and COX-2. COX-1 is related to the synthesis of prostaglandins involved in the protection mechanism of the gastric mucosa, while COX-2 is induced after the inflammatory cells have been activated and participate in the synthesis of inflammation and pain mediators (10). In this context, NSAIDs selective for COX-2 were newly developed, to overcome COX-1 inhibition side effects (11). Acetaminophen was suggested to be the most effective drug that corroborates its pharmacological use in orthodontic movement disturbances, it seems to have no role in the synthesis of prostaglandins(12,13). However, there is still no precise recommendation regarding the most adequate drug for pain control in orthodontic treatment. In this context, determining the NSAID that reduces pain the most without influ- encing the rate of tooth movement becomes essential to optimize the orthodontic treatment (7,13,14). The aims of the present study were to compare the analgesic effect of etoricoxib (a selective NSAID), Ibuprofen (a nonselective NSAID), and acetaminophen on the orthodontic pain generated after archwire placement and/or activation during the alignment and leveling stage, and to find if there is any effect of these analgesics on the rate of teeth movement. Materials and Methods Ethical approval and subjects This randomized, double-blinded, placebo-controlled, prospective study was approved by the Ethical Committee of the College of Dentistry/ University of Baghdad on the 24th February 2020 with Ref. Number 186420. A total of forty patients (age ranged between 18 and 24 years old) who were about to receive fixed orthodontic appliance treatment agreed to enroll in this study. The patients were informed about the pro- cedure through a detailed information sheet, and written informed consent was obtained. Sample size was measured according to a predetermined 80% power of study and 5% significance alpha level. Selection criteria Patients must have a full set of permanent dentitions excluding the third molars. No antibiotic treat- ment for at least four weeks before bonding. No history of systemic diseases or allergies. No current use of steroids or analgesics. Not contraindicated to NSAID. Must not extract teeth at least 4 weeks before bonding. No history of previous orthodontic treatment. Moderate crowding of a maximum of 10mm ac- cording to Little’s irregularity index (LII) (15). This study was done in the Orthodontic Clinic at the College of Dentistry/ University of Baghdad in addition to a private specialized dental center in Baghdad city. Blinding and Randomization Forty-four patients (age ranged between 18 and 24 years old) were recruited; however, three patients did not meet the oral hygiene requirement (GI or PLI >1). The remaining forty-one patients were randomly J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 39 assigned to one of four study groups. A simple non-stratified randomization was done using randomly assign subjects to treatment groups website (https://www.graphpad.com/quickcalcs/randomize1/) with an equal allocation ratio (10 participants per group except group B contained 11patients). The allocation was performed by an independent person. The groups were named as A, B, C, and D and both the patient and the investigator (A.A.M.A), who was responsible for the clinical part of the study, were blinded to the type of analgesic that were given to each group as well as to the grouping itself, which was kept sealed until the completion of data analysis. The drug tablets did not have any markings or labels that represent brand name, and were put in small opaque pill boxes with a sticker containing the name of the group. The pills were put in the boxes by the independent person. Study groups Four experimental groups were predetermined: group A, were given a placebo (starch capsule) once daily (considered as the control group); group B, were given 500 mg acetaminophen (Paracetamol, Pristol House, Unit 3, Canalside, Northbridge Road, Berkhamsted Hertfordshire, United Kingdom) three times daily; group C, were given 400 mg ibuprofen (Denk Pharma, GmbH & Co. KG, Prinzregentenstr., Mün- chen, Germany) three times daily; and group D, were given 60 mg etoricoxib (Arcoxia, Merck Sharp & Dohme B.V., Waarderweg Haarlem, Netherlands) once daily. The lowest recommended dose for each medication was used according to the National Health Service, UK. Drug administration began 1 hour before commencing the bonding procedure and/or archwire change, and were given for three days including the bonding day. Patients were instructed not to take any additional analgesics. A standardized treatment protocol was followed for all participants. The same day after placing the fixed orthodontic appliance, a 0.012-inch archwire was placed for alignment as a starting arch wire and the usual wire consequence was followed (0.014-inch NiTi followed by 0.016-inch NiTi, then 18-inch NiTi) at 6 weeks visit intervals. Archwires were fully tied to the brackets by either ligature wires or elastomeric modules (rotated teeth were ligated with ligature wires). To ensure standardization, any debond happened during the treatment was rebonded within 24 hours, otherwise the case will be ex- cluded. Patients were all reminded about their upcoming visits via cell phone call one day before appoint- ment. Pain assessment Patients recorded the pain perceived on a graded linear visual analogue scale (VAS). Subjects were given routine post-bonding instructions and were thoroughly trained on how to deal with the VAS. Then patients were asked to complete a questionnaire at appropriate intervals during the week after the bond- ing appointment. The questionnaire was in the format of a printed six-page booklet that contained 100 mm horizontal VAS on which patients were asked to mark the degree of discomfort at the indicated time periods. The patients were instructed to make a check on the scale at each time interval to represent the perceived severity of pain during each of the three activities: https://www.graphpad.com/quickcalcs/randomize1/ J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 40 chewing, fitting or occluding on the front teeth, and fitting the back teeth. Incidence and severity of pain were recorded by the patient prior to bonding and drug administration, immediately after bonding, and on the first, second, third and seventh day after bonding. Patients were asked to return the question- naire on the seventh day. This questionnaire was repeated for all activation visits until the end of the alignment stage. A text message reminder was sent to every patient to remind them to mark the questionnaire on the scheduled day. All of the forty patients who enrolled in this study returned their questionnaires, and none of them were recorded to use additional medication. Rate of tooth movement The rate of tooth movement was estimated by measuring the LII for the lower arch before appliance bonding and at each archwire changing visit which was made every 6 weeks till the end of alignment stage directly in patients’ mouth using a four-digit caliper with tenth of a millimeter. The difference between each measurement and its previous one determined the amount of teeth move- ment for that visit. In the present study we have calculated the rate of teeth movement four times before it reached zero crowding. LII is a quantitative method of assessing the anterior teeth irregularity. The technique involves meas- urement of teeth irregularities directly from the patient’s mouth or from the dental cast with a caliper (four-digit caliber with a tenth of a millimeter) held parallel to the occlusal plane. The linear displacement of the adjacent anatomic contact points of the incisors is determined, and the sum of the five measurements represents the Irregularity Index value of a case (15). Statistical analysis The statistical analysis was performed using SPSS 22 on windows 10 software (SPSS Inc., Chicago, Illinois, USA). Data distribution of the VAS scores for pain levels was checked using Shapiro-Wilk test. Descriptive statistics were done for all data. Age differences between groups were evaluated using one-way ANOVA (analysis of variance). All statistical comparisons done included all the three different actions (chewing, fitting anterior teeth and fitting posterior teeth) at each time interval, and were repeated for each archwire changing visit. Comparisons within each drug group over time by means of pain were done using Wilcoxon test with Bonferroni correction, and since 45 multiple comparisons were made for each group, a significance value of P < 0.0011 was considered significant. Differences between the drug groups to compare pain over time were evaluated using Kruskal Wallis test. In the first and third orthodontic visits, ten actions were found to be statistically significant, so Mann Whitney test with Bonferroni correction was done. As sixty multiple comparisons were made, a significant value of P < 0.00083 was considered to be significant. In the second orthodontic visit, 14 actions were found J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 41 statistically significant, the Bonferroni correction of Mann Whitney test indicated considering a signifi- cance value of P < 0.0006 to be significant because 84 multiple comparisons were made. In the fourth or- thodontic visit, only 6 actions were found statistically significant, so Mann Whitney test with Bonferroni correction was done, and a significance value of P < 0.0014 was considered significant, since 36 multiple comparisons were made. Intraclass correlation coefficient (ICC) was used to test the inter-examiner reliability of the LII of a twelve randomly selected patients, LII was remeasured by another investigator at the same visit. The rate of teeth movement was compared between the drug groups using one-way ANOVA test. Results One patient from group B missed to record the pain assessment form and, therefore, were dropped out of the study. The remaining 40 patients who participated in our study completed the whole procedures until the end of their alignment and leveling stage and returned all their pain assessment forms. The CON- SORT flowchart of the current trial is shown in Figure 1. Patient recruitment started in November 2020 and completed in May 2021. Descriptive statistics of the patients’ age for the four groups was calculated as shown in Table 1. The average age for the four groups was not significantly different from each other (P < 0.05). Gender differ- ences were not taken into consideration. Pain levels of the drug groups In all the study groups, the pain level reached its peak after 24 hours of archwire placement and/or activation, this was true through all different actions and in all activation visits. Interestingly, no statisti- cally significant differences (P < 0.0011) were detected between different time intervals for all activities within the same group. Table 1 Descriptive statistics and distribution of age in the study groups. Group Drug N Mea n Std. Devia- tion Min . Ma x. F P A Placebo 10 21 2.055 18 24 0.139 0.936 B Acetamino- phen 10 20.9 1.792 19 24 C Ibuprofen 10 21.4 1.506 19 23 D Etoricoxib 10 21.2 2.098 19 24 Total 40 21.13 1.814 18 24 All the data are presented as mean (95% confidence interval). J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 42 Figure 1. CONSORT flowchart of participants through each stage of the study. Pain levels between the drug groups After the bonding visit and at 24 and 72 hours; ibuprofen, acetaminophen and placebo groups had a comparable pain levels, while etoricoxib group showed a superior analgesic effect over them at chewing and fitting on anterior teeth and the differences were statistically significant (P < 0.00083) (Table 2). After 48 hours etoricoxib, ibuprofen and acetaminophen groups had a comparable analgesic effect during chewing, but all showed significantly (P < 0.00083) higher analgesic effect than placebo group. However, etoricoxib group showed significantly (P < 0.00083) less pain levels than ibuprofen and aceta- minophen groups during fitting on anterior teeth (Table 2). Results after the first activation visit showed significant higher pain levels in the placebo group over other drug groups (P < 0.0006) in all actions. At the first day, Etoricoxib group presented with significantly lower pain levels (P < 0.0006) than ibuprofen group during fitting on anterior teeth, and lower than acet- aminophen group during chewing and fitting on posterior teeth. Ibuprofen group was better in controlling pain than acetaminophen group only during fitting on posterior teeth, the difference was significant (P < 0.0006) (Table 2). J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 43 At the second and third days, etoricoxib and ibuprofen groups had a comparable pain levels, however, these were lower than that of acetaminophen group during fitting on posterior teeth (P < 0.0006), in addi- tion, ibuprofen group showed significantly lower pain levels than acetaminophen group chewing (P < 0.0006) (Table 2). No statistically significant differences were found between the drug groups After the second and third activation visits, except that etoricoxib showed a significantly (P < 0.00083) better analgesic effect than acetaminophen group during fitting on anterior teeth at day 3 (Table 2). Table 2 Pain levels of the four groups at measured functions and time intervals. Action Time Placebo Acetaminophen Ibuprofen Etoricoxib Chewing Day 1 33 (15-55)a 56 (30-75)b 29 (15-40)b 33 (20-45)a 19 (10-25)b 7.2 (0-13)a 9.4 (3-18)b Day 2 58 (50-70)a 66 (25-100)b 28 (15-50)a 20 (10-35)b 24 (5-35)a 3 (0-5)b 14.2 (8-20)a 7.2 (0-18)b Day 3 40 (15-55)b 23 (15-35)a 15 (5-25)b 2 (0-5)b 4.6 (0-10)a 5.2 (0-13)b Day 7 22 (5-40)b 15 (5-25)b 2 (0-5)b Fitting on Front teeth Day 1 56 (45-70)b 54 (45-70)a 22 (20-25)b 21.6 (13-35)a 9.4 (3-18)b Day 2 54 (40-80)a 65 (40-85)b 39 (20-55)a 31 (20-60)a 19 (15-25)b 15.6 (13-20)a 7.2 (0-18)b Day 3 37 (20-80)a 32 (20-55)b 26 (15-60)c 45 (30-60)a 5 (0-10)a 6 (0-15)b 11.2 (8-15)c Day 7 29 (10-60)b 20 (10-30)a 16 (10-20)b 2 (0-5)b 4.6 (0-10)a 4 (0-10)b Fitting on back teeth After bonding/ archwire replacement 21 (10-40)b 2.2 (0-5)b Day 1 59 (25-85)b 21 (20-25)b 9 (0-15)b 7.4 (3-13)b Day 2 64 (50-75)a 64 (20-100)b 11 (0-35)a 19 (15-25)b 2 (0-5)b 13.2 (3-20)a 5.2 (0-13)b Day 3 42 (10-65)b 22 (15-35)b 3 (0-10)b 4 (0-10)b Day 7 27 (10-50)b 2 (0-5)b 3.2 (0-8)b A: Significant differences were found at bonding visit (P < 0.00083), b: Significant differences were found at the first activation visit (P < 0.0006), c: Significant differences were found at the second activation visit (P < 0.00083). J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 44 Rate of teeth movement of the drug groups The mean rate of teeth movement measured at the first visit after 6 weeks of bonding and loading the initial arch wire (first activation) were 2.192 ± 0.735 mm for placebo group, 3.972 ± 1.929 mm for aceta- minophen group, 2.468 ± 1.95 mm for ibuprofen group, and 3.4 ± 1.158 mm for etoricoxib group (Table 3). After the second activation (12 weeks after bonding), the mean rate of teeth movement calculated were 2.09 ± 1.07 mm for placebo group, 2.748 ± 1.3 mm for acetaminophen group, 3.252 ± 0.904 mm for ibuprofen group, and 2.414 ± 0.519 mm for etoricoxib group (Table 3). The mean rate of teeth movement estimated after the third activation (18 weeks of starting alignment and leveling) were 1.92 ± 2.138 mm for placebo group, 1 ± 1.302 mm for acetaminophen group, 1.16 ± 1.055 for ibuprofen group, and 2.266 ± 2.352 mm for etoricoxib group (Table 3). The calculated means of teeth movement after the fourth activation (24 weeks after bonding) were 1.3 ± 0.544 mm for placebo group, 1 ± 0.289 mm for acetaminophen group, 0.9 ± 0.155 mm for ibuprofen group, and 1.25 ± 0.866 mm for etoricoxib group (Table 3). Table 3 Descriptive statistics of the rate of teeth movement in drug groups. Time Groups N Mean Std. Deviation Min. Max. First activation (after 6 weeks) Placebo 10 2.192 0.73525 1.29 3.02 Acetaminophen 10 3.972 1.92894 1.26 6.6 Ibuprofen 10 2.468 1.95013 0.19 5.85 Etoricoxib 10 3.402 1.15817 1.96 5 Total 40 3.0085 1.64139 0.19 6.6 Second activation (after 12 weeks) Placebo 10 2.09 1.06531 1.15 4.05 Acetaminophen 10 2.748 1.30043 1.6 4.7 Ibuprofen 10 3.252 0.90444 2.5 4.9 Etoricoxib 10 2.414 0.51938 1.72 3.25 Total 40 2.626 1.04531 1.15 4.9 Third activation (after 18 weeks) Placebo 10 1.92 2.13817 0 4.4 Acetaminophen 10 1 1.30171 0 2.75 Ibuprofen 10 1.16 1.05536 0 2.5 Etoricoxib 10 2.266 3.92046 0 9.58 Total 40 1.5865 2.35197 0 9.58 Fourth activation (after 24 weeks) Placebo 6 1.3 0.54406 0.9 2 Acetaminophen 4 1 0.28868 0.75 1.25 Ibuprofen 6 0.9 0.15492 0.7 1 Etoricoxib 4 1.25 0.86603 0.5 2 Total 20 1.11 0.49778 0.5 2 All the data are presented as mean (95% confidence interval). J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 45 Rate of teeth movement between the drug groups Intra class correlation coefficient revealed a high reliability level [ICC = 0.976 (95% CI 0.917 ̶ 0.993)] for LII (Table 4). Table 4 Intraclass Correlation Coefficient. Intraclass Correlation 95% Confidence Interval F Test with True Value Lower Bound Upper Bound Value df1 df2 Sig Single Measures 0.953 0.847 0.986 38.578 11 11 0.000 Average Measures 0.976 0.917 0.993 38.578 11 11 0.000 No statistically significant difference (P < 0.05) was detected by ANOVA test between the different exper- imental groups through the whole alignment and leveling period (after the first, second, third and fourth activations after bonding) (Table 5). Table 5 ANOVA test for comparisons of rate of teeth movement between drug groups after different ac- tivation times. Activation Sum of Squares df Mean Square F Sig. First activation Between Groups 20.42 3 6.807 2.895 0.058 Within Groups 84.652 36 2.351 Total 105.072 39 Second activation Between Groups 7.39 3 2.463 2.518 0.074 Within Groups 35.224 36 0.978 Total 42.614 39 Third activation Between Groups 10.988 3 3.663 0.644 0.592 Within Groups 204.75 36 5.688 Total 215.739 39 Fourth activation Between Groups 0.608 3 .0203 0.791 0.517 Within Groups 4.1 16 0.256 Total 4.708 19 Discussion One of the most common complaints among orthodontic patients is pain, especially during the first week of fixed appliance placement and the ongoing activation and archwire changing visits. Many factors have been reported to affect the severity of orthodontic pain such as age, force type, and type of person- ality (16), moreover, the amount of patients’ discomfort and attitude toward treatment found to effect on appliance acceptance (17). Because of such important effect on patients’ compliance, pain management is a priority to ensure a successful orthodontic treatment. J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 46 Pain is a subjective feeling caused and affected by many factors. Several methods were suggested to assess pain in the literature and nearly all of them depends on subjective methods. Like most of the ortho- dontic studies in the literature, VAS was used in the current study to assess pain. It is found to be the most accepted and appropriate over other pain scales because of its ease of measurement and reproducibility (18,19). The current randomized controlled study was conducted on a total of 40 patients who scheduled to have fixed orthodontic appliance therapy. Patients were randomly distributed into one of four experi- mental groups: patients in group A were given placebo (starch capsules), patients in group B administered 500 mg acetaminophen, patients in group C took 400 mg ibuprofen, and patients in group D administered 60 mg etoricoxib; in all four groups, medication was started 1 hour before the bonding/archwire activation procedure and continued for 3 days. All the patients completed the study without using any additional medications. The lowest recommended doses of acetaminophen, ibuprofen and etoricoxib were used to control pain (as suggested by National Health Service, UK). Pain level scores were obtained using VAS at the particular time intervals. The aims of this randomized placebo-controlled study were to assess the efficacy of acetaminophen, ibuprofen (non-selective NSAID), and etoricoxib (highly selective NSAID) ad- ministration on controlling orthodontic pain and their possible effect on the rate of orthodontic tooth movement. The uniqueness of the current study is that pain evaluation was conducted through the whole leveling and alignment period over about 6 months of orthodontic treatment, with repeating the pain control drugs and scoring process during the first week of each visit interval. Rate of teeth movement was also measured through the same leveling and alignment period by measuring the amount of teeth movement at each visit interval. In the present study and through all activation visits, pain started immediately after archwire place- ment or activation and reached its peak after 24 hours in all study groups and all different activities, which markedly reduced at day 7. These findings were similar to previous studies (16,20-24). The average pain score on VAS through the entire study did not exceed 67 on 100 mm scale in placebo group, indicating a moderate pain, which was in agreement with Gupta et al (2014) (24), while in other drug groups the scores were below 44 mm, indicating a mild pain, these results were similar to what found by Salmassian et al (2009) (16). Analgesic effect within the same group of different activities at different time intervals showed no statistically significant difference in all experimental groups. For drug groups pain scores were all mild which made it difficult for the patients to detect a significant reduction in pain, besides, administration timing plays a significant role in the effectiveness of analgesics used for orthodontic pain management due to the differences in their plasma half-life (25). In the current study analgesics were given 1 hour pre- operatively which allow enough time for them to reach a high plasma concentration before pain reached its peak levels. In the placebo group, even though patients didn’t take analgesic medications, no significant difference in pain levels were detected in response to different time intervals through different actions. This is mainly J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 47 due to the psychological effect of placebo drugs which could reach 30-40 % in medical and dental studies (26). Pain evaluation at the bonding visit and at the first visit after bonding revealed that etoricoxib was the most effective drug in pain reduction among other groups, these results were statistically significant for all different actions after 24, 48, and 72 hours, where pain reached its peak levels. This was in agreement with (24) which was the only study in the literature comparing etoricoxib analgesic efficacy in controlling orthodontic pain to other drugs. A systematic review and meta-analysis which published recently con- cluded that placebo is the least effective, while etoricoxib is the most effective analgesic in controlling orthodontic pain (25). At the bonding visit ibuprofen and acetaminophen showed similar results in pain reduction with no statistically significant difference between them, but at the first visit after bonding (6 weeks after bonding) ibuprofen was significantly more effective than acetaminophen in reducing pain in fitting on posterior teeth and on chewing actions after 24, 48, and 72 hours. both drugs were significantly more effective than placebo in those time intervals. When these results compared to previous studies comparing ibuprofen to acetaminophen and placebo, conflicting results were found. Bernhardt et al. (2001) (20) and Bradley et al. (2007) (27) found that ibuprofen administration causes less pain than acetaminophen. Another study which done by Patel et al. (2011) (28) showed similar analgesic effect between acetaminophen and placebo, whereas ibuprofen revealed superior analgesic effect. However, Bird et al. (2007) (29), Salmassian et al. (2009) (16), and Tunçer et al. (2014) (30) have found no statistically significant difference between acetaminophen and ibuprofen. A systematic review done by Xiaoting et al. (2010) (31) concluded that there is no statistical difference detected between ibuprofen, acetaminophen or placebo. Another more recent systematic re- view and meta-analysis indicated that ibuprofen can be effective in reducing pain after separators or arch- wire placement only after 2 and 6 hours compared to placebo, but not at 24 hours. Ibuprofen and aceta- minophen seem to be equally effective (32). The current study showed similar effect in reducing orthodontic pain between the four experimental groups at the second and third visits after bonding (12 and 18 weeks after bonding). It is widely known that teeth movement process happened by blood flow obstruction of the periodon- tal ligament (PDL) at the pressure site leading to the release of PE2 which activate bone resorption process (33). NSAIDs are the most common drugs given to control pain in patients act by blocking the PGE2 pro- duction by inhibiting the COX enzyme and thus disrupting teeth movement as reported in many previous animal studies (34,35). On the other hand, the highly selective COX 2 inhibitor NSAIDs such as etoricoxib suggested to reveal a very little effect on teeth movement in comparison to conventional non-selective NSAIDs (24). Unlike NSAIDs, acetaminophen is not an active anti-inflammatory agent and does not prevent PGE2 production and teeth movement (30,36). Previous studies have shown that acetaminophen consumption for orthodontic pain control has no significant effect on the rate of teeth movement (7,12,13,35,37,38), while ibuprofen administration negatively af- fect the rate of teeth movement (7,12,35,38). However, other studies concluded that ibuprofen and loxoprofen administration longer than two weeks did not have any significant effect on the rate of teeth movement J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 48 (39,40). Recently, it has been demonstrated that only high doses of etoricoxib significantly decrease the rate of teeth movement (41). In the current study, no statistically significant differences were found between the four experimental groups through all activation visits till the end of the leveling and alignment period, these findings indi- cate that etoricoxib, acetaminophen, and ibuprofen drugs have no negative effect on the rate of orthodon- tic teeth movement when prescribed with their recommended doses for three days after each archwire placement and/or activation. The half-life period of the high selective COX-2 inhibitor etoricoxib is 22 hours and reaches its maxi- mum concentration in blood plasma after one hour of oral intake, which is far longer than most of other non-selective NSAIDs (42). This have been shown clearly in the current study, a daily single dose intake of etoricoxib is more effective in orthodontic pain control than ibuprofen or acetaminophen given thrice daily. Furthermore, etoricoxib have the least effect on the gastric mucosa and no inhibitory effect on teeth move- ment. Based on the current randomized study, and for better pain control in patients undergoing orthodontic treatment, it is recommended to prescribe etoricoxib rather than acetaminophen or ibuprofen due to its excellent pain controlling ability without affecting the rate of teeth movement. It is also better to prescribe ibuprofen over acetaminophen because of its superior analgesic effect in the absence of decelerating teeth movement. Conclusion Pain resulting from routine orthodontic treatment is of moderate intensity, and in cases of analgesic pre- scriptions is of mild intensity. Etoricoxib, ibuprofen and acetaminophen are significantly effective in reducing orthodontic pain in the first 3 months of treatment, but have the same effect as the placebo after that. Etoricoxib was the best efficient analgesic in reducing orthodontic pain. Ibuprofen is significantly better than acetaminophen in controlling orthodontic pain. Etoricoxib, ibuprofen and acetaminophen when prescribed with their least recommended doses have no inhibitory effect on the rate of orthodontic teeth movement. Conflict of interest: None. References 1. Brown DF, Moerenhout RG The pain experience and psychological adjustments to orthodontic treatment of preadolescents, adoles- cents and adults. Am J Orthod Dentofacial Orthop 1991; 100:349–356. J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 49 2. Kluemper GT, Hiser DG, Rayens MK, Jay MJ Efficacy of a wax containing benzocaine in the relief of oral mucosal pain caused by orthodontic appliances. Am J Orthod Dentofacial Orthop 2002; 122:359–365. 3. Shenoy N, Shetty S, Ahmed J, Shenoy AK. 2013 The pain management in Orthodontics. J Clin Diagn Res 2013; 7(6): 1258–1260. 4. Krishnan Vinod, Orthodontic pain: from causes to management — a review, Eur J Orthod. 2007; 29: 170–179. 5. Wang J, Jian F, Chen J et al. Cognitive behavioral therapy for orthodontic pain control: a randomized trial. J Dent Res 2012; 91(6): 580–585. 6. Marković E, Fercec J, Šćepan I et al. The correlation between pain perception among patients with six different orthodontic archwires and the degree of dental crowding. Srp Arh Celok Lek 2015; 143(3/4): 134–140. 7. Arias OR, Marquez-Orozco MC. Aspirin, acetaminophen, and ibuprofen: their effects on orthodontic tooth movement. Am J Orthod Dentofacial Orthop 2006; 130(3): 364–370. 8. Arantes GM, Arantes VM, Ashmawi HA et al. Tenoxicam controls pain without altering orthodontic movement of maxillary canines. Orthod Craniofac Res 2009; 12(1): 14–19. 9. Krasny M, Zadurska M, Cessak Get al. Analysis of effect of non-steroidal antiinflammatory drugs on teeth and oral tissues during orthodontic treatment. Report based on literature review. Acta Pol Pharm 2013; 70(3): 573–577. 10. LAUDANNO OM, CESOLARI JA, ESNARRIAGA J, RISTA M, PIOMBO G, MAGLIONE C, ARAMBERRY L, SAMBRANO J, GO- DOY A, ROCASPANA A Gastrointestinal damage induced by celecoxib and rofecoxib in rats. Dig Dis Sci 2001; 46: 779-784. 11. BOMBARDIER C ET AL Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid ar- thritis – VIGOR Study Group. N Engl J Med 2000; 343: 1520-1528. 12. SHETTY N, PATIL AK, GANESHKAR SV, HEGDE S Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study. Prog Orthod 2013; 14: 6-6. 13. Correa AS, Almeida VL, Lopes BMV, Franco A, Matos FR, Quintans-Junior LJ, et al. The influence of non-steroidal anti-inflammatory drugs and paracetamol used for pain control of orthodontic tooth movement: a systematic review. An Acad Bras Cienc. 2017; 89:2851–2863. 14. GONZALES C, HOTOKEZAKA H, MATSUO K, SHIBAZAKI T, YOZGATIAN JH, DARENDELILER MA AND YOSHIDA M. Ef- fects of steroidal and nonsteroidal drugs on tooth movement and root resorption in the rat molar. Angle Orthod 2009; 79: 715-726. 15. Little, R.M. The irregularity index: a quantitative score of mandibular anterior alignment. Am. J. Orthod. 1975; 68, 554–563. 16. Salmassian Reza, Oesterle Larry J., Shellhart W. Craig, and Newman Sheldon M. Comparison of the efficacy of ibuprofen and acet- aminophen in controlling pain after orthodontic tooth movement. Am J Orthod Dentofacial Orthop 2009; 135:516-521. 17. Doll G M, Zentner A, Klages U, Sergl H G. Relationship between patient discomfort, appliance acceptance and compliance in ortho- dontic therapy. J Orofac Orthop 2000; 61: 398–413. 18. Dubner R. Neurophysiology of pain. Dent. Clin. N. Am. 1978; 22: 11–30. 19. Seymour R A, Simpson J M, Charlton J E, Phillips M E. An evaluation of length and end-phrase of visual analogue scales in dental pain. Pain 1985; 21: 177–185. 20. Bernhardt MK, Southard KA, Batterson KD et al. The effect of preemptive and/or postoperative ibuprofen therapy for orthodontic pain. Am J Orthod Dentofacial Orthop 2001; 120:20–27. 21. Aslihan M, Erdinc E, Dincer B. Perception of pain during orthodontic treatment with fixed appliances. Eur J Orthod 2004; 26:79–85 2. 22. Omur P, Ihya AI. Pain control during fixed orthodontic appliance therapy. Angle Orthod 2005; 75:214–219. 23. Polat O, Karaman AL, Durmus E. Effects of pre-operative ibuprofen and naproxen sodium on orthodontic pain. Angle Orthod 2005; 75:791-6. J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 50 24. Gupta M, Kandula S, Laxmikanth SM, Vyavahare SS, Reddy SB, Ramachandra CS. Controlling pain during orthodontic fixed appli- ance therapy with non-steroidal anti-inflammatory drugs (NSAID): a randomized, double-blinded, placebo-controlled study. J Orofac Orthop. 2014; 75(6):471-6. 25. Sandhu SS, Piepho HP, Khehra HS. Comparing the effectiveness profile of pharmacological interventions used for orthodontic pain relief an arm-based multilevel network meta-analysis of longitudinal data. Eur J Orthod. 2017; 39(6):601–614. 26. Bouncher Y. Pharmacology and pain. Rev. orthop. dento-fac. 1999; 33: 123–141. 27. Bradley R L, Ellis P E, Thomas P, Bellis H, Ireland A J, Sandy J R. A randomized clinical trial comparing the efficacy of ibuprofen and paracetamol in the control of orthodontic pain. Am J Orthod Dentofacial Orthop 2007; 132: 511–517. 28. Patel S, McGorray S P, Yezierski R, Fillingim R, Logan H, Wheeler TT. Effects of analgesics on orthodontic pain. Am J Orthod Den- tofacial Orthop 2011; 139: e53–e58. 29. Bird S E, Williams K, Kula K. Preoperative acetaminophen vs ibuprofen for control of pain after orthodontic separator placement. Am J Orthod Dentofacial Orthop 2007; 132: 504–510. 30. Tunçer Zeynep, Polat-Ozsoy Omur, Demirbilek Muge, Bostanoglu Ebru. Effects of various analgesics on the level of prostaglandin E2 during orthodontic tooth movement. Eur J Orthod 2014; 36: 268–274. 31. Xiaoting L, Yin T, Yangxi C. Interventions for pain during fixed orthodontic appliance therapy. A systematic review. Angle Orthod 2010; 80: 925–932. 32. Angelopoulou M. V., Vlachou V., Halazonetis D.J. Pharmacological management of pain during orthodontic treatment: a meta- analysis Orthod Craniofac Res 2012; 15: 71–83. 33. Reitan K, Rygh P 2007 Biomechanical principles and reactions. In: Proffit W R, Fields H W (eds). Contemporary Orthodontics, 2nd edn, Mosby Year Book, St Louis, pp. 122. 34. Chumbley AB, Tuncay OC. The effect of indomethacin (an aspirin-like drug) on the rate of orthodontic tooth movement. Am J Orthod. 1986; 89:312–14. 35. Kehoe MJ, Cohen SM, Zarrinnia K, Cowan A. The effect of acetaminophen, ibuprofen and misoprostol on prostaglandin E2 synthesi s and the degree and rate of orthodontic tooth movement. Angle Orthod. 1996; 66(5):339–50. 36. Joint Formulary Committee British National Formulary 73. London: BMJ Publishing and RPharmS 2017. 37. Stabile AC, Stuani MB, Leite-Panissi CR, et al. Effects of shortterm acetaminophen and celexocib treatment on orthodontic tooth movement and neuronal activation in rat. Brain Res. Bull. 2009; 79: 396–401. 38. Kaklamanos Eleftherios G., Makrygiannakis Miltiadis A., Athanasiou Athanasios E. Do analgesics used for the pain experienced after orthodontic procedures affect tooth movement rate? A systematic review based on animal studies. Orthod Craniofac Res. 2020; 23:143–150. 39. Brunson TD. (2008) Effect of cyclooxygenase inhibitors on rat root resorption and tooth movement. PhD Thesis, University of South California, USA. 40. Yamamoto T, Kaku M, Sumi H, et al. Effects of loxoprofen on the apical root resorption during orthodontic tooth movement in rats. PLoS One 2018; 13: e0194453. 41. Kirschneck C, Küchler EC, Wahlmann U, et al. Effects of the highly COX-2-selective analgesic NSAID etoricoxib on the rate of or- thodontic tooth movement and cranial growth. Ann. Anat. 2018; 220: 21–28. 42. Patrignani, P., Capone, M.L., Tacconelli, S. Clinical pharmacology of etoricoxib: a novel selective COX2 inhibitor. Expert Opin. Phar- macother. 2003; 4, 265–284. J. Bagh. Coll. Dent. Vol. 34, No. 2. 2022 Abdaljawwad and Al-Groosh 51 فعالية مسكنات األلم على إدراك األلم ومعدل حركة األسنان تجربة سريرية عشوائية. ضياء حسين الكروش د.ا.د.عاصم عباس عبد الجواد، : المستخلص من التطور من االدوية المسكنة الخلفية: يعتبر األلم احد اكثر اآلثار الجانبية لعالج تقويم االسنان بالرغم تم تقديم العديد مجال تقويم االسنان. العلمي في قائية. الهم االكبر فيما يخص للسيطرة على االلم الناتج عن تقويم االسنان وتشمل البراسيتامول و االدوية المضادة لاللتهاب الغير ستيرويدية االنتقائية والغير انت .حركة االسنان هذه االدوية هو انها تؤثر سلبا على معدل تأثيرهم على الهدف: الهدف من هذه الدراسة هو لتقييم ومقارنة تأثير كل من البراسيتامول والبروفين واالتوريكوكسب على االحساس بااللم ومعرفة مدى .معدل حركة االسنان في مرحلة تسوية وانتظام االسنان اختيارهم تم مريضا اربعون والطرق: النشاء(، المواد )كبسوالت وهمي عالج مجموعات: اربع احد على عمياء وبطريقة عشوائية بصورة وتوزيعهم ملغم مرة واحدة في اليوم. تم اعطاء االدوية قبل 60ملغم ثالث مرات في يوم، اإلتوريكوكسب 400ملغم ثالث مرات في يوم، البروفين 500البراسيتامول ت لمدة ثالثة ايام. تم استخدام مقياس التناظرية البصرية للتعبير عن مستوى االلم بعد وضع سلك التقويم ، وفي اليوم ساعة من وضع جهاز التقويم واستمر جهاز حتى نهاية االول والثاني والثالث والسابع. تم قياس مقدار فهرس ليتل لقياس تراكب االسنان قيل وضع جهاز تقويم االسنان وعند كل زيارة لتفعيل ال .سوية وانتظام االسنانمرحلة ت ى. اإلتوريكوكسب النتائج: جميع مجاميع االدوية الثالث اظهرت مستوى الم اقل من مجموعة العالج الوهمي بعد وضع جهاز التقويم وعند زيارة التفعيل االول ين مجموعات االدوية ومجموعة العالج الوهمي عند اظهر اقل مستوى لاللم من بين جميع االدوية يأتي من بعده البروفين. ال وجود الختالف احصائي بارز ب .زيارات التفعيل الثانية والثالثة. ال وجود الختالف احصائي بارز بين جميع المجموعات االربع فيما يخص معدل تحرك االسنان ملغم 60زيارتين االولى والثانية، وان االتوريكوكسب اإلستنتاج: جميع االدوية الثالث فعالة فقط في السيطرة على االلم الناتج من عالج تقويم االسنان في ال .مرة واحدة في اليوم هو االفضل. جميع االدوية الثالث ليس لها تأثير على معدل حركة االسنان عند استعمالها ضمن الحد االدنى الموصى به