Etanercept (Enbrel) to Treat Pain and Swelling After Third Molar Extraction
Etanercept (Enbrel) to Treat Pain and Swelling After Third Molar Extraction
This study will evaluate the effects of the anti-inflammatory drug etanercept (Enbrel) on
 relieving pain and swelling after oral surgery. The Food and Drug Administration has approved
 Enbrel for treating symptoms of rheumatoid arthritis, including pain.

 Healthy volunteers 16 to 35 years of age who require third molar (wisdom teeth) extractions
 may be eligible for this study. Participants must not be allergic to aspirin or to
 non-steroidal anti-inflammatory drugs (NSAIDs). Candidates will be screened for eligibility
 with a medical history and oral examination, including X-rays if needed.

 Participation in the study requires four clinic visits: two for surgery and two for
 follow-up:

 Visit 1:

 Patients will have ultrasound pictures taken to measure cheek size. One hour before surgery,
 they will receive a dose of either 25 milligrams (mg) of Enbrel; 15 mg of the standard pain
 medicine Toradol; or a placebo (salt-water) through an arm vein. A local injection of an
 anesthetic (lidocaine) will be given before surgery to numb the mouth, and a sedative
 (Versed) will be infused through a vein to induce sleepiness. When the anesthetic takes
 effect, a small piece of tissue will be removed from the inside of the cheek, and then the
 upper and lower molars on one side of the mouth will be extracted. After surgery, a small
 piece of tubing will be placed in the lower extraction site, from which samples will be
 collected to measure chemicals involved in pain and inflammation. Patients will stay in the
 clinic for 4 hours after surgery while the anesthetic wears off and will complete pain
 questionnaires during that time. If, an hour after surgery, patients have pain that is not
 relieved by the treatment given before surgery, they may receive acetaminophen (Tylenol) and
 codeine for pain. Another biopsy will be taken (under local anesthetic) from the inside of
 the cheek when pain occurs or at the end of the 4-hour observation period. The tubing then
 will be removed and the patient discharged with Tylenol and codeine for pain.

 Visit 2:

 Patients will return to the clinic in the morning 48 hours after the oral surgery for a 1- to
 2-hour visit. They will fill out questionnaires, undergo ultrasound imaging of both cheeks
 and have another biopsy taken from the inside of the cheek on the operated side.

 Visits 3 and 4:

 Three weeks after the first surgery patients will schedule extraction of the two wisdom teeth
 on the other side of the mouth, and the procedures for visits 1 and 2 will be repeated.
The proposed investigation is a randomized, double-blind, placebo and positive-controlled
 within-subjects design clinical study to evaluate the role of the cytokine tumor necrosis
 factor (TNF) in acute inflammation using a specific TNF receptor antagonist, etanercept
 (Enbrel, Immunex Corporation, Seattle, WA). The goal of this study is to determine whether
 inhibition of TNF bioactivity can attenuate acute inflammation. The anti-inflammatory and
 adverse effects of etanercept, a recombinant TNF receptor fusion protein, will be evaluated
 using a model of tissue injury, the oral surgery model. Briefly, healthy volunteers referred
 for third molar extraction will undergo the surgical extraction of third molars with local
 anesthesia and conscious sedation. At the completion of the surgical procedure, a
 microdialysis probe will be placed under the mucogingival flap previously elevated for the
 surgical procedure and subjects will be observed for pain and swelling over the course of
 four hours following surgery. Tissue biopsies prior to and following surgery will be obtained
 from the buccal mucosa. Etanercept or control will be administered parenterally one hour
 prior to surgery. Tissue levels of pro-inflammatory cytokines, growth factors, and
 inflammatory mediators will be measured at time intervals postoperatively. Pain and swelling
 will be assessed postoperatively over the course of four hours and at 48 hours. Demonstration
 of amelioration of pain, swelling, and/or changes in levels of tissue mediators will be taken
 as evidence of an acute anti-inflammatory effect of etanercept. Since the fusion protein
 (hereafter, TNFR:fc) specifically binds TNF-alpha and prevents its interaction with cellular
 receptors, changes in the inflammatory cascade and clinical endpoints of inflammation may
 provide insight into role of TNF-alpha in the pathophysiology of acute inflammation and its
 clinical sequela.
INCLUSION CRITERIA

 Male or female volunteers referred for extraction of third molars willing to undergo two
 surgical appointments for the extraction of unilateral third molars.

 Between the ages of 16 to 35 years (based upon eruption patterns and age-related
 complications associated with surgical extraction of third molars).

 In good general health - ASA status 1 or 2 (healthy subjects based upon criteria for safe
 outpatient conscious sedation).

 Willing to undergo observation period for four hours postoperatively.

 Willing to return at 48 hours for measurement of pain, swelling, and tissue biopsy.

 Willing to return for a total of four visits beyond the screening visit.

 EXCLUSION CRITERIA

 Pregnant or lactating females.

 Current mental disorder or substance abuse.

 Allergy to aspirin or NSAIDs.

 Chronic use of medications confounding assessment of the inflammatory response or analgesia
 (antihistamines, NSAIDs, steroids, antidepressants).

 Presence of chronic debilitating disease (such as diabetes, rheumatoid arthritis, liver
 disease, etc).

 Presence of symptomatic tooth suggesting infection or inflammation.

 Unusual surgical difficulty encountered during the surgical procedure.