Abstract
The authors examined whether ketoprofen administered 60 min before surgical extraction of the lower wisdom teeth provides effective postsurgical analgesia and reduces rescue analgesic intake compared with ketoprofen administered 60 min after surgery or placebo. The 96 patients were placed into three groups: pre-group (ketoprofen 60 min preoperatively); post-group (ketoprofen 60 min postoperatively); and no-group (placebo). Study interventions had a significant effect on pain sensations in the 12 h after surgery. The initial onset of pain was significantly delayed only in the post-group. Pain intensity at the first onset of pain was significantly lower only in the post-group. Patients in the pre- and post-groups required significantly less rescue analgesic than those in the no-group. Ketoprofen administered after third molar surgery provides more effective pain control than ketoprofen administered before the surgery or placebo.
Trauma accompanying tissue damage during surgery and subsequent inflammation induce local nociceptor sensitization. Accumulation of active mediators (e.g., prostanoids, kinins, serotonin, histamine, substance P and reactive oxygen species ) leads to ‘neurogenic oedema’ and induces primary hyperalgesia, which may be clinically observed as an increased sensitivity to mechanical and heat stimuli arising from the site of injury.
In oral surgery, primary hyperalgesia results from the peripheral sensitization of mucosal and periosteal receptors by a range of inflammatory mediators, such as the prostaglandins. Secondary hyperalgesia follows the central sensitization of trigeminal nucleus neurons and supra-spinal structures, such as the rostral ventral medulla. Secondary hyperalgesia may be observed over time, whilst primary hyperalgesia is demonstrable within a couple of hours after injury. Prostaglandins are synthesized rapidly after tissue injury and appear in significant concentrations 1 h after trauma . Recent studies have demonstrated a significant role for prostaglandins within the central nervous system (CNS) and in the peripheral nervous system . Medications that inhibit prostaglandin production may prevent primary and/or secondary hyperalgesia, reducing postoperative pain and discomfort and the consumption of rescue analgesics. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the synthesis of prostaglandins by inhibiting two different isoforms of cyclo-oxygenase (COX-1 and COX-2), thus blocking the nociceptive response to endogenous mediators of inflammation; the effect is greatest in tissues that have been subjected to injury and trauma . This process may represent a pathway that can be used to prevent primary hyperalgesia.
S avage and H enry claim that the only useful way to assess the preemptive analgesic effect of a specific medication is to evaluate the postoperative pain experienced when medication is administered before injury compared with the administration of the same medication after injury. It seems that more unbiased results would be obtained from a comparison of the analgesic effect of the same medication administered before and after surgery compared with no-treatment at all. Previous studies that attempted to assess the efficacy of preemptive analgesia in oral surgery employed a protocol in which medication was administered before the injury compared with placebo administered before the injury or the same drug administered after surgery . Such a study design could be the reason for the lack of a consensus regarding whether preemptive analgesic interventions are more effective than conventional (postsurgery) regimens in managing acute postoperative pain . T aylor and B rennan rightly claim that the reduction in pain that follows the use of a medication given before injury, with no comparison with the effect of the same medication given after injury, demonstrates an analgesic effect, but not a preemptive analgesic effect. To date, studies that compare the analgesic effect of pre-treatment, post-treatment and no-treatment with the same medication in oral surgery have been scarce in the literature .
The purpose of this study was to test the hypothesis that oral ketoprofen administered before third molar surgery would produce an effective preemptive analgesic effect compared with placebo administration or oral ketoprofen administered after surgery. The authors decided to use 100 mg of ketoprofen, a short-acting and short-onset NSAID that has strong COX-1 and COX-2 inhibition potential. The maximum daily dose of ketoprofen is 300 mg. Ketoprofen is widely used in dentistry, and many previous studies have proved that ketoprofen is an effective medication for treating pain in oral surgery ; but none of these studies has assessed the preemptive effect of its action. The goal was to assess if ketoprofen has a real preemptive analgesic effect and if it can prevent primary hyperalgesia in oral surgery procedures.
Materials and methods
One hundred generally healthy individuals volunteered, using a signed document, to take part in the trial. The study protocol followed a prospective, single-centre, randomized, double-blinded and active-controlled clinical trial design. The patients, the statistician and the surgeon performing the qualification, operative procedure and follow-up examination were all blinded with regard to which patients had received which form of treatment. One hundred opaque, sequentially numbered envelopes were used for the concealed allocation of patients to trial groups. Each envelope contained the group assignment for one patient, which was determined in advance by a random number table. Identical, non-marked capsules with 100 mg ketoprofen or 100 mg placebo were prepared and coded in a professional pharmaceutical laboratory. All surgical procedures were carried out in an identical manner by the same specialist oral surgeon, using identical sets of instruments. Patients did not receive any extra financial compensation for participating in the trial.
A flow chart of patient recruitment according to the CONSORT statement is shown in Fig. 1 . The basic criterion for including a patient in the study was a need for surgical extraction of a retained lower third molar. The molars to be extracted had not caused inflammation and were in at least a partial bony impacted state, requiring bone removal. The criteria for exclusion were: age under 18 or over 60 years; pregnancy; allergy to ketoprofen, aspirin or any other NSAID; lactose intolerance (lactose was the main component of the placebo); any digestive diseases; inflammation in the area of the tooth to be extracted; and any antibiotic or analgesic intake within the previous 7 days. Patients were not administered any antibiotic prophylaxis for the surgical procedure. Qualification, elimination of contraindications and written consent were obtained by the blinded surgeon performing the surgery.
Using these methods of randomization and allocation concealment, the patients were assigned to one of the following 3 groups. In the pre-treatment group (pre-group), patients received 100 mg ketoprofen orally 60 min preoperatively, followed by 100 mg placebo orally 60 min postoperatively. In the post-treatment group (post-group), patients received 100 mg placebo orally 60 min preoperatively, followed by 100 mg ketoprofen orally 60 min postoperatively. In the no-treatment group (no-group), patients received 100 mg placebo orally 60 min preoperatively, followed by 100 mg placebo orally 60 min postoperatively.
The time from ketoprofen/placebo administration to anaesthesia was standardized to 60 min for every patient. Investigators confirmed that the pain prior to the beginning of the anaesthesia and immediately after the completion of surgery was absent or negligible. All patients received perineural anaesthesia into the inferior alveolar and lingual nerves and infiltrative anaesthesia in the vestibular region. Local anaesthesia was delivered using 3.6 ml of a 4% solution of articaine with 1:200,000 epinephrine. After 15 min, surgery was initiated and its duration (the period between incision of the mucosa and completion of the last suture) was recorded in the patient’s record. The surgical procedure was standardized and involved creating a triangular mucoperiosteal flap followed by bone removal using a drill cooled with water. After extraction, the wound was rinsed with a sterile solution of physiological saline, and after achieving local haemostasis, the wound was sutured.
Each patient was given an explanation about how to measure pain intensity on the visual analogue scale (VAS) of 0–100 mm, with 0 representing no pain and 100 representing the worst pain imaginable. Study participants were asked to record the pain intensity score every hour for 12 h after completion of the surgery as measured by the number of fixed time intervals during which they experienced pain in every hour (primary endpoint). Additional analyses included the first and the second episode of pain that compelled the patient to take a rescue analgesic (500 mg paracetamol capsule) recorded on the VAS, as well as the time from termination of the surgery to these episodes (secondary endpoints). The total rescue analgesic intake in every group in the 12 h postsurgery and the total number of patients who took no rescue analgesic were recorded.
Statistical analysis was performed with Statistica 8.0. PL (StatSoft Polska, Krakow 2007). Demographic data was analysed using the χ 2 and ANOVA tests, where appropriate. The Kruskal–Wallis rank test was used to analyse the duration of surgery, quantity of total analgesic intake, time to the first/second pain episode and the level of pain in each of the fixed time intervals. The differences in rescue analgesic intake between the groups were analysed using the Mann–Whitney U -test. To establish the mutual influence of both within-group (along the time axis) and between-group factors, the pain score differences between groups during the entire 12 h observation period were assessed using analysis of variance with repeated measures (RM-ANOVA, within-between design). Differences in VAS scores between groups at each of the fixed time intervals were tested with Scheff’s post hoc test. In all calculations, a P- value of less than 0.05 was considered significant.
Results
One hundred patients entered the trial, of whom 4 did not check-in for the follow-up examination. In all, complete data sets from 96 patients were statistically analysed. There were no significant differences in gender ( P = 0.77, χ 2 test) or age ( P = 0.63, ANOVA) between the three groups ( Table 1 ). The Kruskal–Wallis rank test did not reveal any statistically significant differences between groups with regard to the time of surgery ( P = 0.92) ( Table 1 ). The baseline VAS scores did not show any significant differences between groups ( P = 0.95, Kruskal–Wallis rank rest). No statistically significant difference in the demographic factors, mean duration of the surgery and the baseline pain scores permitted a comparative assessment of the study results.
| Pre-group | Post-group | No-group | P -values | |
|---|---|---|---|---|
| Number of patients ( n (%)) | 34 (35.4%) | 30 (31.2%) | 32 (33.3%) | 0.8 |
| Age (years) | 22.6 ± 0.7 | 21.5 ± 0.5 | 23.1 ± 0.8 | 0.63 |
| Sex (female/male) | 24/10 | 20/10 | 24/8 | 0.77 |
| Time of surgery (min) | 16.81 ± 3.41 | 14.71 ± 3.01 | 15.03 ± 3.29 | 0.92 |
| Total analgesic intake (mg) | 750 ± 221.5 | 716.6 ± 281.7 | 1093.75 ± 411.3 | 0.03* |
| Numer of patients who took no rescue analgesic ( n (%)) | 6 (6.3%) | 8 (8.3%) | 3 (3.1%) | 0.04* |
| Time to first analgesic intake (min) | 336.75 ± 10.43 | 409.93 ± 12.69 | 228.85 ± 7.08 | 0.0013* |
| Time to second analgesic intake (min) | 542.51 ± 16.81 | 466.42 ± 14.43 | 377.46 ± 11.69 | 0.477 |
| VAS-pain scores at the first onset of pain (mm) | 45.7 ± 10.53 | 33.1 ± 7.91 | 57.7 ± 12.43 | 0.031* |
| VAS-pain scores at the second onset of pain (mm) | 36.4 ± 8.73 | 30.7 ± 9.01 | 38.5 ± 7.75 | 0.717 |
The Kruskal–Wallis rank test revealed significant differences in the VAS scores between the groups between the fourth and twelfth hour postsurgery ( P < 0.05) in each fixed time interval in this period of study assessment. The study interventions had a significant effect on pain sensation during the 12 h postsurgery: RM-ANOVA (within-between design) for the VAS scores 12 h postsurgery revealed significant differences for the effect of time ( F = 13.57195; P < 0.001; within-group factor), the effect of group ( F = 164.9457; P < 0.001; between-group factor) and the interaction of group × time ( F = 5.5644; P < 0.001). Scheff’s post hoc test revealed significant differences in VAS scores, specifically at each of the fixed time intervals between the fourth and twelfth hour postsurgery ( P < 0.001) ( Fig. 2 ).
There were also statistically significant differences between the three groups with regard to the time when the first rescue analgesic was taken ( P = 0.0013, Kruskal–Wallis rank test) ( Table 1 ). The exact analysis revealed that there was a significant difference between post/no-groups ( P = 0.001), whilst the P -value for the difference between pre/no-groups only slightly exceeded the statistically significant value ( P = 0.058). There were no statistically significant differences between pre- and post-groups in this regard. Further analysis revealed statistically significant differences between the groups in pain intensity at the first episode of rescue analgesic intake ( P = 0.031, Kruskal–Wallis rank test) ( Table 1 ). A detailed comparison discovered a significant difference only between post- and no-groups ( P = 0.039; Mann–Whitney U -test). No differences in this regard were revealed for the comparison between pre- and no-groups ( P = 0.146; Mann–Whitney U -test) or between pre- and post-groups ( P = 0.89; Mann–Whitney U -test).
No statistically significant difference between the three groups was revealed with regard to the time of the second episode of rescue analgesic intake ( P = 0.477, Kruskal–Wallis rank test) ( Table 1 ). No statistically significant differences between any of the groups were revealed with respect to pain intensity at the second episode of rescue analgesic intake ( P = 0.717) ( Table 1 ).
The Kruskal–Wallis rank test revealed significant differences between groups with regard to total rescue analgesic intake ( P = 0.03) ( Table 1 ). Further analysis demonstrated significant differences between pre/no-groups ( P = 0.03) and post/no-groups ( P = 0.02) (Mann–Whitney U -test). There were no statistically significant differences between pre/post-groups in this regard ( P > 0.05; Mann–Whitney U -test).
Using the Kruskal–Wallis rank test, statistically significant differences between the groups with regard to the number of patients who did not need any analgesic intake in the 24 h postsurgery were found ( P = 0.04; Table 1 ). Further analysis revealed significant differences only between pre/no-groups ( P = 0.01; Mann–Whitney U -test) and post/no-groups ( P = 0.023; Mann–Whitney U -test). No statistically significant differences between pre/post-groups were revealed in this regard ( P > 0.05; Mann–Whitney U -test).
None of the patients had any serious complications due to the study’s pharmacological interventions, the existence of which would have resulted in exclusion from the study.
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