International Journal of Oral & Maxillofacial Surgery
Volume 39, Issue 7 , Pages 647-652, July 2010

Preemptive effect of ketoprofen on postoperative pain following third molar surgery. A prospective, randomized, double-blinded clinical trial

  • T. Kaczmarzyk

      Affiliations

    • Department of Oral Surgery, Jagiellonian University Medical College, Krakow, Poland
    • Corresponding Author InformationAddress: Tomasz Kaczmarzyk, Department of Oral Surgery, Jagiellonian University Medical College, Montelupich 4, 31-155 Krakow, Poland. Tel.: +48 12 4245468; fax: +48 12 4245499.
    web address
    • ,
  • J. Wichlinski

      Affiliations

    • Department of Oral Surgery, Jagiellonian University Medical College, Krakow, Poland
    • ,
  • J. Stypulkowska

      Affiliations

    • Department of Oral Surgery, Jagiellonian University Medical College, Krakow, Poland
    • ,
  • M. Zaleska

      Affiliations

    • Department of Oral Surgery, Jagiellonian University Medical College, Krakow, Poland
    • ,
  • J. Woron

      Affiliations

    • Department of Clinical Pharmacology, Jagiellonian University Medical College, Krakow, Poland

Accepted 9 February 2010. published online 25 March 2010.

Article Outline

Abstract 

The authors examined whether ketoprofen administered 60min before surgical extraction of the lower wisdom teeth provides effective postsurgical analgesia and reduces rescue analgesic intake compared with ketoprofen administered 60min after surgery or placebo. The 96 patients were placed into three groups: pre-group (ketoprofen 60min preoperatively); post-group (ketoprofen 60min postoperatively); and no-group (placebo). Study interventions had a significant effect on pain sensations in the 12h 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.

Keywords: preemptive analgesia, ketoprofen, third molar surgery, oral surgery, pain, visual analogue scale

 

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 species3, 10, 16, 39) leads to ‘neurogenic oedema’20 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 1h after trauma23, 29. Recent studies have demonstrated a significant role for prostaglandins within the central nervous system (CNS) and in the peripheral nervous system37. 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 trauma16, 18. This process may represent a pathway that can be used to prevent primary hyperalgesia.

Savage and Henry29 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 injury5, 14 or the same drug administered after surgery33, 34. 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 pain26. Taylor and Brennan36 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 literature15.

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 100mg 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 300mg. Ketoprofen is widely used in dentistry, and many previous studies have proved that ketoprofen is an effective medication for treating pain in oral surgery4, 24, 32, 35; 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.

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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 100mg ketoprofen or 100mg 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 statement1 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 100mg ketoprofen orally 60min preoperatively, followed by 100mg placebo orally 60min postoperatively. In the post-treatment group (post-group), patients received 100mg placebo orally 60min preoperatively, followed by 100mg ketoprofen orally 60min postoperatively. In the no-treatment group (no-group), patients received 100mg placebo orally 60min preoperatively, followed by 100mg placebo orally 60min postoperatively.

The time from ketoprofen/placebo administration to anaesthesia was standardized to 60min 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 3.6ml of a 4% solution of articaine with 1:200,000 epinephrine. After 15min, 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 0–100mm, 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 12h 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 (500mg 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 12h 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 χ2 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 12h 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.

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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, χ2 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.

Table 1. Demographic and objective measurement data.
Pre-groupPost-groupNo-groupP-values
Number of patients (n (%))34 (35.4%)30 (31.2%)32 (33.3%)0.8
Age (years)22.6±0.721.5±0.523.1±0.80.63
Sex (female/male)24/1020/1024/80.77
Time of surgery (min)16.81±3.4114.71±3.0115.03±3.290.92
Total analgesic intake (mg)750±221.5716.6±281.71093.75±411.30.03*
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±10.43409.93±12.69228.85±7.080.0013*
Time to second analgesic intake (min)542.51±16.81466.42±14.43377.46±11.690.477
VAS-pain scores at the first onset of pain (mm)45.7±10.5333.1±7.9157.7±12.430.031*
VAS-pain scores at the second onset of pain (mm)36.4±8.7330.7±9.0138.5±7.750.717

Figures present mean±SEM, or number of patients with percentage. The asterisks denote statistical significance.

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 12h postsurgery: RM-ANOVA (within-between design) for the VAS scores 12h 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).

  • View full-size image.
  • Fig. 2. 

    Pain scores (VAS) recorded at specific time intervals postsurgery. Values are means±SEM. Significant differences in the VAS scores between the groups in each of the fixed time intervals in the period between the fourth and twelfth hour postsurgery (P<0.05).

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 24h 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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Discussion 

Many pharmacological strategies have been developed to prevent peripheral and central sensitization, thereby attenuating or even preventing the postoperative amplification of pain sensations16. The most prevalent methods include administration of: NSAIDs25, which prevent peripheral sensitization by reducing prostaglandin synthesis at the site of surgery; regional anaesthetics7, which block afferent nociceptive impulses prior to incision; opioids19, 27, which modulate afferent input by blocking the postsynaptic receptors and decreasing neurotransmitter release or by activating inhibitory pathways; and NMDA-receptor antagonists11, which inhibit activation of N-methyl-d-aspartate (NMDA) receptors in the human spinal cord, thus preventing the main mechanism of central sensitization. Other strategies include alpha2 receptor antagonists and cholecystokinin16.

Pain that follows oral cavity surgical procedures can be optimally controlled by NSAIDs4, 8, 30, therefore it seems that the most promising strategy for preemptive analgesia in oral surgery is the administration of NSAIDs before commencement of the surgical procedure6. Previous studies on NSAID-preemptive analgesia in oral surgery have yielded conflicting results. Some have proved the preemptive effect of ketorolac25, piroxicam13, parecoxib9 and rofecoxib with dexamethasone22, others have disputed the preemptive effect of diclofenac5, naproxen33 and ibuprofen28, 38. Some studies have not supported the preemptive effect of a particular NSAID for pain intensity in the postoperative period but have proved a reduction in rescue analgesic consumption13 or delayed time before the first onset of pain12. None of these studies has compared the analgesic effect of NSAIDs with three different administration times: before surgery, after surgery, and no administration of the drug at all. The first well-controlled attempt to assess the analgesic effect of pre-treatment, post-treatment and no-treatment with NSAIDs in third molar surgery was performed by Jung et al.15. They compared the preemptive analgesic effect of 370mg talniflumate administered 1h preoperatively, 1h postoperatively or not at all. They suggested that the analgesic effect of talniflumate administered preoperatively was no greater than when the drug was administered postoperatively. They recommended that scheduling postoperative analgesic dosing before pain development is adequate for postoperative analgesia, arguing that preoperative analgesic administration is unnecessary for the surgical extraction of third molars. The results of the present study support this opinion: ketoprofen administered 60min postoperatively provides the same level or greater of pain control compared with the same drug administered 60min preoperatively. The former treatment was significantly more effective compared with no administration of the medication. It would be interesting to compare the effect of pre- and postsurgery ketoprofen dosing with another group of patients receiving medication either before or after third molar surgery. It has been argued that preemptive analgesia, commencing before surgery and continuing during the postoperative period, prevents the establishment of peripheral and central sensitization2, 17.

These outcomes are similar to observations on NSAID-preemptive analgesia in other surgical procedures in the oral cavity. Vogel et al.38 compared the efficacy of medicating with ibuprofen immediately before surgery to medicating immediately after surgery on postoperative pain associated with periodontal surgery. They found that administration of ibuprofen immediately before or immediately after periodontal surgery significantly delays pain onset compared with placebo, with postsurgical dosing demonstrating a significantly greater delay of pain onset compared with presurgical dosing.

Pain following third molar surgery is usually most severe between 6–84, 31 or 3–5h21 after completion of surgery and gradually decreases afterwards. If there are no inflammatory complications, pain is usually absent or negligible after the second postsurgical day. One of the potential goals of preemptive analgesia is to prevent pain sensation in the period when it is at its peak. Results of the present study indicate that patients receiving ketoprofen postoperatively exhibited a significant delay in the first onset of postoperative pain compared with those who did not receive ketoprofen. There were differences (not statistically significant) when comparing the pre- and no-groups. Likewise, pain intensity at the first onset of pain was significantly lower in the post-group compared with the other groups. This suggests that ketoprofen has a greater potential analgesic effect when administered 60min postoperatively rather than 60min preoperatively. This observation could be connected to the compound's short plasma half-life and rapid effect, which peaks at 60–90min after dosage32; blood levels of a single dose administered prior to surgery may not be sufficient for the postsurgical period when prostaglandins are maximally produced at the site of injury. The administration of ketoprofen in the pre-group occurred 60min before the administration of local anaesthesia. Therefore, the effect of ketoprofen peaked during the action of the local anaesthetic; the analgesic effect of ketoprofen may have been masked by the local anaesthesia. In contrast, ketoprofen administered 60min postsurgery (about 90min after application of local anaesthetic) may be able to reveal its analgesic action. Since the desired effect of presurgically administered NSAID is to prevent prostaglandin production in the area of injury and thereby reduce peripheral sensitization, it seems that ketoprofen is not effective enough when administered 60min before surgery. It is effective in this regard when administered 60min after the completion of surgery. Accordingly, if significant concentrations of prostaglandins are observed in the injured tissues about 1h after injury29, the preemptive effect of NSAIDs may be strongest when the drug is administered after surgery. This may be true with regard to surgeries of brief duration (e.g., third molar surgeries), which last an average of about 15–20min. When the surgery time is longer than 60min, it seems that NSAIDs should be administered before or during the surgery. Similar suggestions have been put forward by Jung et al.15, who suggested that local anaesthetics might also have a preemptive analgesic effect in reducing sensory inflow from the periphery to the CNS, thus masking the preemptive analgesic influence of NSAIDs. Therefore, patients receiving medication postsurgery may experience the longest period of analgesia because the NSAID was administered at the longest interval after local anaesthesia15.

There were significant differences amongst the groups with respect to the total postoperative analgesic intake: patients receiving ketoprofen (pre- or postoperatively) took significantly less rescue analgesic than those receiving placebo. Hutchison et al.13 also found that after administration of 40mg piroxicam 2.5h before third molar surgery, a significantly greater number of patients did not require opioid analgesia after the operation compared with patients given the placebo. They also observed that the time to first postoperative analgesia was longer in those patients who had received piroxicam.

The results presented here indicate that dosing with ketoprofen 60min before or 60min after third molar surgery delays the onset of pain in comparison with placebo, with dosing after surgery demonstrating a significantly greater delay of pain onset compared with dosing presurgically. Unlike presurgical dosing, dosing after surgery significantly decreases mean pain intensity for 12h after third molar surgery compared with placebo. The total analgesic intake during the 12h postsurgery is significantly lower irrespective of the ketoprofen dosing schedule compared with placebo. Ketoprofen administered after third molar surgery provides more effective pain control than ketoprofen administered before the surgery or placebo.

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Competing interests 

None declared.

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Funding 

Grant of the Jagiellonian University (K/ZDS/00519).

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Ethical approval 

Bioethics Committee of the Jagiellonian University (KBET/133/L/2006).

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PII: S0901-5027(10)00064-0

doi:10.1016/j.ijom.2010.02.019

International Journal of Oral & Maxillofacial Surgery
Volume 39, Issue 7 , Pages 647-652, July 2010

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