This study will evaluate the ability of a new non-steroidal anti-inflammatory drug (NSAID)
called rofecoxib to prevent pain following third molar (wisdom tooth) extraction. The Food
and Drug Administration approved rofecoxib in 1999 to treat the symptoms of arthritis,
menstrual cramps, and pain.
Healthy normal volunteers between 16 and 35 years of age in general good health who require
third molar (wisdom tooth) extraction may be eligible for this study. Candidates will be
screened with a medical history and oral examination, including dental x-rays as needed to
confirm the need for third molar removal.
Participants will have all four wisdom teeth extracted, and a biopsy (removal of a small
piece of tissue) will be taken from the inside of the cheek around the area behind the lower
wisdom tooth. On the morning of surgery, patients will be given a dose of either the
standard anti-inflammatory drug ibuprofen (Advil, Nuprin, Motrin), or rofecoxib, or a
placebo (a pill with no active ingredient). Before surgery, they will be given a local
anesthetic (lidocaine) in the mouth and a sedative (midazolam) through an arm vein.
After the surgery, patients will remain in the clinic for up to 4 hours to monitor pain and
the effects of the drug. Patients will complete pain questionnaires. Patients whose pain is
unrelieved an hour after surgery may request and receive morphine intravenously (through a
vein). After 4 hours, patients will be discharged with additional pain medicines (Tylenol
with codeine and the study drug) and instructions for their use. They will also be given a
pain diary to record pain ratings and medications taken at home. A clinic staff member will
telephone patients at home the morning after surgery to ensure they are rating their pain
intensity at the proper time and are taking their medications as instructed.
Patients will return to the clinic 48 hours after surgery with the pain diary and pain
relievers. At this visit, another biopsy will be taken under local anesthetic.
Pain and inflammation are predictable sequelae following tissue injury, such as surgery.
Conventional treatment for intraoperative and postoperative control of pain includes local
anesthetic administered preoperatively and analgesics administered postoperatively.
Disadvantages of these approaches include pain during the interval when the effect of local
anesthesia dissipates and the postoperatively administered analgesic takes effect and
adverse effects of opioid-containing analgesics in ambulatory patients. Research over the
past two decades has demonstrated that administering nonsteroidal anti-inflammatory drugs
(NSAIDs) preoperatively significantly reduces the intensity and the duration of
postoperative pain up to eight hours (Dionne et al., 1978 and Jackson et al., 1989).
Parallel clinical investigations suggest that the pre-emptive treatment with a long-acting
local anesthetic or an NMDA-antagonist reduces pain at 24 to 72 hours post-surgery (Gordon
et al., 1997; Yamamoto et al., 1993; Gordon et al., 1999). This proposed clinical trial will
use the oral surgery model to assess the therapeutic efficacy of pre-emptive and preventive
treatment with a potent selective COX-2 inhibitor, rofecoxib (Vioxx® (Registered
Trademark)), given prior to and following third molar extractions to reduce postoperative
pain at 24 and 48 hours post-surgery.
This study is a double-blind, randomized control trial with parallel groups using placebo,
ibuprofen, or rofecoxib. Rofecoxib 50 mg will be administered PO 90 minutes before surgery
in the Clinical Center at NIH and another 50 mg will be self-administered 24 hours later by
the subjects at their homes. This regimen is predicted to suppress the onset and intensity
of post-operative dental pain to a greater extent than placebo or a non-selective
COX-1/COX-2 inhibitor (ibuprofen). The analgesic effect of the drugs will be estimated by
hourly observations over the first four hours after surgery using two different measures of
pain intensity, the category scale and a visual analog scale (VAS). It is hypothesized that
the pre-emptive administration of a selective COX-2 inhibitor, rofecoxib will inhibit the
development of central and peripheral sensitization following tissue injury which manifests
as hyperalgesia at later time points.
Male or female volunteers referred for third molar extraction willing to undergo 3 visits:
1 screening visit, 1 surgical appointment, and 1 follow-up research-related appointment.
Between the ages of 16 to 35 years (based upon eruption patterns and age-related
complications associated with surgical extraction of third molars)
In general good health- American Society of Anesthesiologists (ASA) status I or II
(healthy subjects based upon criteria for safe administration of out-patient conscious
Willing to undergo observation period for four hours post-operatively
Willing to complete a 100 mm visual analog scale and a category scale every hour for the
first 4 post-operative hours, and again at 24 and 48 hours
Willing to have a preoperative biopsy on the day of surgery and a postoperative biopsy at
Willing to return 48 hours to return completed pain diaries and for the postoperative
Sum total of the assessment of surgical difficulty ratings (Screening visit) must be
between 8 to 14 in order to evaluate subjects experiencing similar pain levels.
Allergy to aspirin or NSAIDS
Pregnant or lactating females
History of peptic ulcers and GI bleeding
Chronic use of medications confounding the assessment of the inflammatory response or
analgesia ( antihistamines, NSAIDS, steroids, antidepressants, sulfa drugs)
Presence of a clinical signs suggestive of infection or inflammation
Unusual surgical difficulty
Surgical difficulty assessment rating less than 8 or greater than 14