Abstract
This study aimed to compare the effect of nimesulide and ketoprofen on inflammatory parameters related to the surgical removal of third molars. A split-mouth, prospective, randomized, double-blind study was conducted in patients undergoing removal of four third molars. Eighteen eligible patients were allocated to one of two groups to receive treatment two times a day with either ketoprofen 100 mg or nimesulide 100 mg for a period of 3 days. The rescue medication intake (number) and pain intensity were evaluated at 6, 12, 24, and 48 h, and at 7 days postoperatively. Swelling and maximum mouth opening were evaluated at 24 h, 72 h, and 7 days postoperatively. The peak pain score occurred at 6 h after surgery in the nimesulide group and at 12 h in the ketoprofen group. There was no statistically significant difference between the groups, although pain relief was observed after 48 h in the nimesulide group and after 7 days in the ketoprofen group. For each group, there was a statically significant difference in pain scores among the studied periods ( P < 0.0001). None of the patients required rescue medication. There was a statistically significant difference in maximum mouth opening between the preoperative and postoperative periods ( P < 0.0001). Ketoprofen and nimesulide were effective at controlling pain, swelling, and trismus after the surgical removal of third molars.
The surgical removal of impacted third molars is considered the most common outpatient procedure among oral surgeries. Normally, an inflammatory reaction with pain, swelling, and trismus is observed as a result of this procedure. The removal of third molars is commonly associated with a significant change in quality of life, particularly during the first three postoperative days. Therefore, it is necessary to take measures to control the postoperative inflammatory events. Such measures include cryotherapy, laser application, and NSAIDs (non-steroidal anti-inflammatory drugs).
Nimesulide (4-nitro-2-phenoxy methane sulfonanilide) belongs to the group of sulfanilamide derivatives, differing from other NSAIDs by presenting a sulfonanilide radical rather than a carboxylic radical. This drug is a partially selective cyclooxygenase 2 enzyme (COX-2) inhibitor, used for the treatment of acute pain, such as that associated with osteoarthritis. It is currently accepted for use in countries of different regions of the world, including Europe, Latin America, and Asia. Nimesulide has shown efficacy in the treatment of acute pain associated with different diseases, such as back pain, toothache, postoperative pain and inflammation, and headache and migraine. Its efficiency has been evaluated in more than 200 clinical studies, which have included more than 90,000 patients with inflammatory and acutely painful conditions. The use of nimesulide in the symptomatic treatment of inflammatory pain is supported by the rapid onset of the analgesic drug effect, which becomes apparent at 15 min after its administration. Thus, nimesulide is a valuable option when the rapid relief of pain is required.
Ketoprofen is an effective inhibitor of cyclooxygenase and prostaglandin synthesis, demonstrating antipyretic, analgesic, and anti-inflammatory properties. This drug has been used in the treatment of musculoskeletal disorders, and evidence from clinical studies suggests that ketoprofen is as effective as other anti-inflammatories in the reduction of postoperative pain and discomfort. Following third molar removal, this drug relieves pain approximately 25.5 min after its administration.
Several clinical trials have been conducted to compare the actions of acetaminophen, ibuprofen, ketorolac, meloxicam, ketoprofen, and nimesulide in the control of inflammatory events after third molar surgery. To date, only one study has been performed to compare the effects of nimesulide and ketoprofen on the inflammation caused by this surgical procedure, and the drugs were administered rectally. Therefore, we present the results of a split-mouth, prospective, randomized, double-blind trial aimed at assessing and comparing the effects of orally administered nimesulide and ketoprofen on pain, swelling, and trismus in patients undergoing the surgical removal of four third molars under local anaesthesia.
Materials and methods
Study design and sample
The present prospective, single-centre, randomized, double-blind pilot study using a split-mouth design was conducted on patients recruited from the division of oral and maxillofacial surgery of the university hospital who required third molar extraction. This study was approved by the university hospital ethics committee and was performed in accordance with the Declaration of Helsinki. Patient recruitment was conducted between April 2011 and June 2012 and followed the guidelines of the CONSORT statement.
This study included healthy subjects (ASA classification I; American Society of Anesthesiologists) of both genders, aged 18–35 years, with an indication for removal of their four third molars and no periodontal disease. The subjects were able and willing to cooperate with the protocol and to sign an appropriate written informed consent form. Furthermore, to standardize the sample, each patient had to have similar patterns of tooth and root formation, position, and impaction degree between the upper and lower third molars of the right and left sides of the mouth. Patients were excluded if they fulfilled at least one of the following criteria: smoker, pregnant or breast-feeding, using medications that interact with the drugs used in this study, have orthodontic bands on the second molars, a known allergy to NSAIDs, a systemic chronic disease, signs of any pre-existing acute inflammatory or infectious condition, or a history of NSAID use in the past 21 days. Patients who did not follow the indicated recommendations or whose surgery exceeded 2 h were removed from this study. Patients who did not return for reassessment were also removed.
Patient data were recorded preoperatively and according to a standardized clinical examination, and included gender, age, systemic conditions, periodontal status, haemogram parameters, platelet count, international normalized ratio (INR) value, and blood glucose. Orthopantomograms were required to evaluate tooth variables such as position, Pell and Gregory and Winter classifications, tooth/root formation, and degree of impaction.
Patients were scheduled for surgery at two separate clinical sessions (one side at a time) at least 3 weeks apart. Each person had both upper and lower third molars removed at the same time on the involved side. Subjects were allocated to one of two groups according to a computer-generated randomization code to receive treatment two times a day with either ketoprofen 100 mg or nimesulide 100 mg (one tablet every 12 h for 3 days). The study drugs were dispensed as identical tablets by a blinded collaborator. Prior to the surgical procedure, the method of allocation concealment of the right and left sides of the mouth was followed, as described by Bezerra et al. Antibiotic prophylaxis was not adopted for the surgical procedure.
Surgical overview
All patients were submitted to a standardized surgical technique performed in an outpatient setting under local anaesthesia, followed by strict biosafety control. One surgeon with 5 years of experience in dentoalveolar surgery performed all of the surgical procedures. The same surgical procedure was adopted for both sides of the mouth, aiming to reduce the bias related to the intraoperative trauma. Local anaesthesia with 2% mepivacaine associated with 1:200,000 epinephrine (three cartridges) was administered. A mucoperiosteal flap was raised and bone removal and/or tooth sectioning was performed. The surgical wound was closed using a 4–0 silk suture.
After surgery, 750 mg of acetaminophen was allowed as rescue medication for 7 days if necessary. The postoperative recommendations were carefully read and explained to the patient, in particular the need for a liquid and cold diet for 24 h, rigorous oral hygiene, and to avoid mouthwash. Patients were informed that they should contact the surgeon by telephone in the case of persistent bleeding or any other complications such as fever.
Outcome measures
The primary outcome of the study was the occurrence of postoperative pain. Measurement of this outcome considered both the pain intensity and the need for rescue analgesia. Postoperative pain intensity was measured using a 10-cm visual analogue scale (VAS) ranging from 0 (absence of pain or discomfort) to 10 (maximum pain or discomfort). Before starting the treatment, each patient received an explanation about how to measure pain intensity on this scale. Study participants were asked to record the pain intensity score at 6, 12, 24, 48, and 72 h, and 7 days following surgery. Additional analyses included the evaluation of time to re-medication, which was defined by Ong et al. as ‘the time from the end of surgery until the intake of rescue medication became necessary for the patient’. The number of patients requiring acetaminophen after the surgical procedure and the number of analgesics consumed during the study period were recorded.
The secondary outcome was the occurrence of postoperative inflammatory events. The following measurements were performed to evaluate postoperative swelling on the facial side receiving surgery ( Fig. 1 ): tragus to the soft pogonion (Tr–Pog’), tragus to the external corner of the eye (Tr–Exo), tragus to the nasal border (Tr–Al), tragus to the labial commissure (Tr–Che), angle of the mandible to the external corner of the eye (Go–Exo), angle of the mandible to the nasal border (Go–Al), angle of the mandible to the soft pogonion (Go–Pog’), and angle of the mandible to the labial commissure (Go–Che). The differences between the preoperative values (baseline) and those measured at 24 h, 72 h, and 7 days after surgery were compared.
To estimate trismus, maximum mouth opening was measured in millimetres between the upper and lower central incisors using a calibrated sliding caliper (TheraBite Range-of-Motion Scales), preoperatively (baseline) and at 24 h, 72 h, and 7 days after surgery.
Statistical analysis
Standard statistical evaluation included the Kolmogorov–Smirnov test to evaluate the normality of the distributions. Pain scores and facial distances did not follow the Gaussian pattern of normality, differing from maximum mouth opening, which did. The Mann–Whitney test was used for comparisons of pain scores and facial distances between the ketoprofen and nimesulide groups. The Friedman test (Dunn post hoc test) was used to assess the same variables (pain score and facial distances) among each of the fixed postoperative time intervals. One-way analysis of variance (ANOVA; Tukey post hoc tests) and the t -test were used to assess the means of maximum mouth opening. All data were expressed as the mean ± standard deviation (SD). Statistical significance was set at P < 0.05.
Results
The composition of the final sample in the present study was in accordance with the characteristics of clinical trials using ‘split-mouth’ as the study design. The experimental units randomly allocated to interventions in split-mouth models are expressed by divisions of the mouth (e.g. dental arches/sides), allowing better control of individual biological responses with a reduced number of recruited individuals. A total of 744 patients were assessed for eligibility in this study ( Fig. 2 ); 724 did not meet the study criteria, one was removed because orthodontic treatment was started with banding of the second molars, and one did not return for follow-up. Among the excluded persons, there were cases with overlapping exclusion criteria. Thus, an order of priority was adopted for the exclusion criteria.
The study sample comprised 18 patients. There were 16 females (88.9%) and two males (11.1%) and they ranged in age from 18 to 35 years (mean age 19 ± 4.4 years). The lower third molars ( n = 36) were characterized as 1A ( n = 16), 1B ( n = 10), 2A ( n = 4), and 2B ( n = 6) according to the Pell and Gregory classification ( P > 0.05; Chi-square test), and as horizontal ( n = 2), mesioangular ( n = 16), and vertical ( n = 18) according to the Winter classification ( P > 0.05; Chi-square test). The upper third molars ( n = 36) were characterized as A ( n = 22), B ( n = 8), and C ( n = 6) according to the Pell and Gregory classification ( P > 0.05; Chi-square test), and as mesioangular ( n = 2), vertical ( n = 10), and distoangular ( n = 24) according to the Winter classification ( P > 0.05; Chi-square test). The average duration of surgery was 29.9 (±7.2) min; extractions on the left side took 30.4 (±7.3) min, while those on the right side took 29.4 (±7.3) min.
Pain intensity
Comparisons of pain intensity between the groups at each observation time point did not reveal any statistically significant difference ( Table 1 ). Figure 3 illustrates the change in the mean postoperative pain scores across the different observation time points of the study (6, 12, 24, 48, and 72 h, and 7 days). The comparison of all observation periods among each group and between the groups showed a statistically significant difference using the Friedman test ( P < 0.0001). In the ketoprofen group, the Dunn post hoc test identified a difference between the time points of 6 h and 7 days, and between 12 h and 7 days ( Fig. 4 A ). In the nimesulide group, a statistically significant difference was found between the time points of 6 h and 48 h, 6 h and 72 h, and 6 h and 7 days ( Fig. 4 B).
| Period after surgery | Pain score (mean ± SD) | P -value | Test | |
|---|---|---|---|---|
| Ketoprofen | Nimesulide | |||
| 6 h | 2.611 ± 1.914 a | 2.611 ± 1.852 a , b , c | 0.9872 | Mann–Whitney |
| 12 h | 2.889 ± 3.085 d | 2.000 ± 2.612 | 0.4395 | Mann–Whitney |
| 24 h | 1.667 ± 2.249 | 1.278 ± 2.191 | 0.4856 | Mann–Whitney |
| 48 h | 1.611 ± 2.547 | 1.444 ± 2.791 b | 0.5836 | Mann–Whitney |
| 72 h | 0.9444 ± 1.798 | 0.8889 ± 1.937 c | 0.7707 | Mann–Whitney |
| 7 days | 0.1111 ± 0.4714 a , d | 0.2222 ± 0.6468 a | 0.5744 | Mann–Whitney |
| Total | 1.639 ± 2.318 | 1.407 ± 2.209 | 0.4653 | Mann–Whitney |
| P -value | <0.0001 | <0.0001 | Friedman/post hoc Dunn | |
a Statistically significant difference between 6 h and 7 days.
b Statistically significant difference between 6 h and 48 h.
c Statistically significant difference between 6 h and 72 h.
d Statistically significant difference between 12 h and 7 days.
Time to rescue analgesia
After the standardized administration of the study drugs in both groups, only one of the patients required a drug for rescue analgesia during the observation period of the study. The patient requiring a rescue drug was removed from the analyzed sample because she took a drug other than acetaminophen 750 mg.
Facial swelling and trismus
At each observation point, there was no statistically significant difference in the mean linear distances between the two studied groups ( P > 0.05). However, comparing all observation periods between themselves and by group ( Table 2 ), a statistically significant difference was observed for the distances Tr–Al (ketoprofen, P = 0.0029), Tr–Che (ketoprofen, P = 0.0026; nimesulide P < 0.0001), Tr–Pog’ (ketoprofen, P < 0.0001; nimesulide, P = 0.0008), Go–Exo (nimesulide, P = 0.0437), Go–Al (nimesulide and ketoprofen, P < 0.0001), Go–Pog’ (ketoprofen, P = 0.0087; nimesulide, P < 0.0001), and Go–Che (ketoprofen, P = 0.0004; nimesulide, P < 0.0001). Table 3 shows the differences between measurements in the preoperative and postoperative periods.
| Distances | P -value a | |
|---|---|---|
| Ketoprofen | Nimesulide | |
| Tr–Exo | 0.1873 | 0.9311 |
| Tr–Al | 0.0029 b | 0.1621 |
| Tr–Che | 0.0026 b | <0.0001 b |
| Tr–Pog’ | <0.0001 b | 0.0008 b |
| Go–Exo | 0.0775 | 0.0437 b |
| Go–Al | <0.0001 b | <0.0001 b |
| Go–Pog’ | 0.0087 b | <0.0001 b |
| Go–Che | 0.0004 b | <0.0001 b |
| Distances | Difference in cm (mean ± SD) | P -value a | |
|---|---|---|---|
| Ketoprofen | Nimesulide | ||
| 24 h | |||
| Tr–Exo | 0.05 ± 0.08 | 0.03 ± 0.05 | 0.2576 |
| Tr–Al | 0.17 ± 0.50 | 0.18 ± 0.19 | 0.9356 |
| Tr–Che | 0.35 ± 0.25 | 0.33 ± 0.29 | 0.5112 |
| Tr–Pog’ | 0.38 ± 0.34 | 0.33 ± 0.32 | 0.3627 |
| Go–Exo | 0.21 ± 0.33 | 0.12 ± 0.26 | 0.4090 |
| Go–Al | 0.33 ± 0.33 | 0.30 ± 0.33 | 0.9235 |
| Go–Pog’ | 0.14 ± 0.29 | 0.28 ± 0.26 | 0.1637 |
| Go–Che | 0.38 ± 0.28 | 0.33 ± 0.94 | 0.5033 |
| 72 h | |||
| Tr–Exo | 0.04 ± 0.15 | 0.01 ± 0.10 | 0.2863 |
| Tr–Al | 0.89 ± 0.32 | 0.12 ± 0.12 | 0.2313 |
| Tr–Che | 0.25 ± 0.28 | 0.25 ± 0.26 | 0.7000 |
| Tr–Pog’ | 0.33 ± 0.27 | 0.28 ± 0.27 | 0.4718 |
| Go–Exo | 0.12 ± 0.35 | 0.07 ± 0.25 | 0.6295 |
| Go–Al | 0.24 ± 0.30 | 0.22 ± 0.28 | 0.8978 |
| Go–Pog’ | 0.06 ± 0.24 | 0.12 ± 0.23 | 0.7347 |
| Go–Che | 0.27 ± 0.32 | 0.24 ± 0.91 | 0.7484 |
| 7 days | |||
| Tr–Exo | 0.02 ± 0.15 | 0.02 ± 0.08 | 0.9151 |
| Tr–Al | 0.33 ± 0.42 | 0.08 ± 0.13 | 0.1026 |
| Tr–Che | 0.89 ± 0.26 | 0.09 ± 0.16 | 0.6861 |
| Tr–Pog’ | 0.07 ± 0.23 | 0.09 ± 0.20 | 0.6015 |
| Go–Exo | 0.03 ± 0.09 | 0.01 ± 0.20 | 0.7558 |
| Go–Al | 0.03 ± 0.09 | 0.00 ± 0.17 | 0.2135 |
| Go–Pog’ | 0.02 ± 0.07 | 0.00 ± 0.12 | 0.1448 |
| Go–Che | 0.04 ± 0.17 | 0.05 ± 0.82 | 0.9487 |
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