Central sensitization refers to persistent post-injury changes in the central nervous system resulting in greater pain sensitivity. The concept of preemptive analgesia is defined as a treatment that prevents establishment of central sensitization by providing analgesic coverage during the perioperative period of surgery. Previous acute pain studies using the oral surgery model have shown that suppression of postoperative pain, not intra-operative nociceptive barrage, diminishes the development of sensitization at 24 to 48 hours post-surgery. During the intermediate postoperative period, the nociceptive input from both surgical insult and inflammation leads to central sensitization, yet their relative contributions have not been clearly evaluated. The proposed study is designed to evaluate the relative impact of surgical insult and the subsequent inflammation on postoperative pain. The relative contribution of each of these nociceptive processes provides a basis for postoperative pain management and the development of preemptive strategies.

All subjects (N = 136) will be healthy volunteers scheduled for third molar extractions. Using a double-blinded, randomized, parallel study design, subjects will be randomized into four groups. All patients will receive local anesthesia injections preoperatively (either 2% lidocaine or 0.5% bupivacaine) to manage surgical pain in conjunction with a preemptive medication (either 50 mg of rofecoxib or placebo) to control postoperative inflammation. The first dose of preemptive medication will be taken by mouth 90 minutes prior to conscious sedation and extractions, and later self-administered once a day for the next 48 hours. The analgesic effect of the drugs will be assessed in the clinic every 20 minutes for the first four hours after extractions, and then self-assessed at 24, and 48 hours after surgery using two pain intensity assessment instruments: category scale and visual analog scale (VAS). Microdialysis will be performed with sample collection concurrent with pain report over the immediate postoperative period of four hours. Two biopsies will be performed: preoperatively, and postoperatively at 48 hours. The combination regimen with bupivacaine and rofecoxib is predicted to maximally suppress the onset and intensity of postoperative dental pain to a greater extent than all other groups through a blockade of the nociceptive input from both surgery and inflammation. It is hypothesized that this preemptive treatment will maximally inhibit the development of central sensitization following tissue injury which manifests as hyperalgesia at later time points. It is also hypothesized that the administration of rofecoxib (a cyclooxygenase-2 selective anti-inflammatory medication) will reduce post-surgical pain experienced at later time points to a greater extent than suppression of the intra-operative nociceptive barrage alone (by bupivacaine), suggesting that suppression of inflammation plays a more pivotal role than attenuating nociception due to tissue injury in diminishing central sensitization.