Evaluation of a TNF-Alpha Modulator for Clinical and Molecular Indicators of Analgesic Effect
Evaluation of a TNF-Alpha Modulator for Clinical and Molecular Indicators of Analgesic Effect
This study will evaluate the role of thalidomide, a tumor necrosis factor (TNF)-alpha
 modulator, on severe inflammation and relief of pain following extraction of wisdom teeth.
 TNFs are substances that affect the pathways of pain. This study involves an experimental
 group in which patients will be given thalidomide or a placebo (an inactive substance); a
 negative control group receiving the medication diazepam or a placebo; and a positive control
 group receiving diazepam or ibuprofen.

 Patients who are males ages 16 to 35, who are not allergic to aspirin or other nonsteroidal
 anti-inflammatory drugs (known as NSAIDs), sulfites, or certain anesthetics, and who in good
 health may be eligible for this study. Females are not eligible, owing to the risks that
 thalidomide presents to unborn children. To minimize the risk of fetal malformations, male
 patients who participate must use a condom during sexual intercourse for 4 weeks following
 the study and must not donate blood for 4 weeks.

 The medications used in the study will be given 1 hour before surgery. Then after the wisdom
 teeth are removed, a small piece of tubing will be placed into both sides of the patient's
 mouth where the teeth were removed. Every 20 minutes, for the next 6 hours, the researchers
 will collect inflammatory fluid from the tubing, to measure for changes in anti-inflammatory
 action. If they request pain relievers, patients will receive the medication ketorolac
 (Toradol), used for short-term treatment of moderately severe acute pain. Side effects of
 thalidomide include fatigue, dizziness, and rash. The use of ibuprofen and ketorolac may
 include the risk of gastrointestinal ulcers and bleeding. Diazepam can cause involuntary
 muscle movements and drowsiness, as well as dizziness lasting for up to 24 hours after it has
 been used as sedation. Patients will be instructed not to try to walk alone or to try to
 drive a vehicle during that period. Other risks related to participation in this study
 include those usually experienced with removal of wisdom teeth-that is, pain and swelling,
 bruising from insertion of the sedative into a vein (if needed), possible infection at the
 extraction site, prolonged bleeding, and numbness.

 Benefits from participating are having wisdom teeth removed at no cost as well as close
 monitoring before and after surgery. Results from the study may help people in the future by
 improving the management of pain following surgery.
The proposed investigation is a randomized, double-blind, placebo and positive-controlled
 clinical study to evaluate the role of the cytokine tumor necrosis factor alpha (TNF-alpha)
 modulator, thalidomide, in acute inflammation and analgesia. The analgesic effect of
 thalidomide, a putative TNF-alpha modulator, will be evaluated using a model of tissue
 injury, the oral surgery model. Briefly, healthy males referred for third molar extraction
 will undergo the surgical extraction of third molars using standard surgical methods. 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 over the course of six hours following surgery. Thalidomide or control will
 be administered one hour prior to surgery. Tissue levels of pro-inflammatory cytokines, and
 inflammatory mediators will be measured at time intervals postoperatively concomitant with
 pain measurements. Pain will be assessed postoperatively over the course of six hours.
 Demonstration of amelioration of pain is the primary outcome measure; changes in levels of
 tissue mediators will be taken as evidence of an acute anti-inflammatory effect of
 thalidomide. Based on our previous work with the fusion protein etanercept (TNFR:fc) which
 specifically binds TNF-alpha and prevents its interaction with cellular receptors, similar
 changes in the inflammatory cascade and clinical endpoints of inflammation may provide
 insight into the activity of thalidomide on acute inflammation and its clinical sequela,
 pain.
INCLUSION CRITERIA:

 -  male patients referred for extraction of third molars willing to undergo surgical
 extraction of all indicated third molars

 -  a minimum of one partial-bony impacted third molar, with a total difficulty score
 total of not less than 8

 -  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 six hours postoperatively

 EXCLUSION CRITERIA:

 -  females

 -  current mental disorder or substance abuse

 -  allergy to aspirin, NSAIDs, or sulfonamide

 -  history of peptic ulcers and GI bleeding

 -  concurrent use of agents which may potentiate the sedative effect of study drugs,
 alcohol, opioids, benzodiazapines

 -  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

 -  excessive surgical difficulty encountered during the surgical procedure, resulting in
 a difficulty score of 5 for any tooth

 -  patients with acute narrow angle glaucoma, and open angle glaucoma who are not
 receiving therapy