Protocol Number: 04-D-0124

Title:

Proinflammatory Gene Expression and Prostanoid Levels in a Clinical Model of Tissue Injury

Number:

04-D-0124

Summary:

This study will evaluate how well different medications work to relieve pain following third molar (wisdom tooth) extraction. Scientists believe that hormone-like substances called prostanoids contribute to pain following oral surgery. Prostanoids are produced by cyclooxygenase (COX) enzymes. This study will examine how different medicines inhibit the COX enzymes and reduce the amount of prostanoids, and thus the amount of inflammation and pain. The study will also look at genetic factors involved in the production of prostanoids and the response to pain medication. (Only the bottom two wisdom teeth are extracted for this study. Patients whose top wisdom teeth also need to be removed will have those teeth extracted, also free of charge, at least 2 weeks after the first surgery.)

Healthy normal volunteers between 16 and 35 years of age who are in general good health and who require third molar extraction may be eligible for this study. Candidates are screened with a medical history and oral examination, including dental x-rays as needed to confirm the need for third molar removal.

On the morning of surgery, patients have blood drawn to obtain DNA for genetic study. Women of childbearing age have a urine pregnancy test. One hour before surgery, patients receive a dose of rofecoxib (Vioxx® (Registered Trademark)), acetaminophen (Tylenol® (Registered Trademark)), or placebo (a pill with no active ingredient). A half-hour before surgery, they receive either a standard painkiller called keterolac (Toradol® (Registered Trademark))) or placebo through an arm vein. All patients also receive the sedative midazolam (Versed® (Registered Trademark)), also through an arm vein, to induce drowsiness and a local anesthetic (lidocaine) to numb the mouth. After the mouth is numbed, but before the wisdom teeth are extracted, a biopsy (removal of a small piece of tissue) is conducted in the area of the cheek next to the wisdom tooth.

After the surgery, a small piece of tubing is placed into both extraction sites. Every 20 minutes for the next 3 hours, inflammatory fluid is collected from the tubing to measure chemicals that are believed to cause pain and swelling. Patients complete questionnaires every 20 minutes to rate their pain. Those who still have pain an hour after surgery may request and receive a "rescue drug" called tramadol (Ultram® (Registered Trademark)) for pain relief. Patients remain in the clinic from 3 to 6 hours to monitor the effects of the study drugs as the anesthetic wears off.

After surgery a second biopsy is done to measure any changes in the chemicals being produced in response to the surgery. For this biopsy, patients are assigned to one of two groups - one group has the second biopsy within 3 hours of surgery, before taking the rescue drug, and the other group returns to the clinic the next morning for a biopsy 24 hours after surgery. Patients in the second group leave the clinic after surgery with two pain medications (tramadol and the study drug) and forms to record pain ratings at home. They are permitted to take only the pain medications provided and only at certain times.

At the end of their participation in the study, all patients are given the pain medication flurbiprofen (Ocufen® (Registered Trademark)) to take at home.

Sponsoring Institute:

National Institute of Dental And Craniofacial Research (NIDCR)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Male or female volunteers referred for third molar extraction willing to undergo 2 or 3 visits: 1 screening visit; 1 surgical appointment; and possible 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 sedation)

Willing to undergo observation period for three hours postoperatively

Ability to complete a 100 mm visual analog scale and a category scale every 20 minutes for the first 3 postoperative hours

Willing to have a microdialysis probe placed beneath the surgical flap during the first 3 hours post-surgery

Willing to have a preoperative biopsy on the day of surgery, and a postoperative biopsy either within 3 hours or at 24 hours following surgery

Willing to return, if needed, 24 hours post-operation for the postoperative biopsy

Must have two lower partial bony impacted wisdom teeth fully covered by intact soft tissue (rating equals 3) or fully bony impacted (rating equals 4) wisdom teeth (mandibular third molars)

As assessed at the screening visit, the sum of the mandibular third molar surgical difficulty ratings must be between 6 to 8 in order to evaluate subjects experiencing similar pain levels

EXCLUSION CRITERIA:

Patients who are allergic to aspirin, NSAIDs, sulfites, or amide anesthetics

Patients who have had asthma, or hives

Patients who are pregnant or nursing

Patients with history of peptic ulcers and/or GI bleeding

Chronic use of medications confounding the assessment of the inflammatory response or analgesia, for example, NSAIDs, COX-2 inhibitors, antihistamines, steroids, antidepressants

Patients who have significant psychiatric history

Patients who have a clinical signs suggestive of infection, inflammation, or pre-existing pain at either extraction site

Patients with severe kidney disease

Patients who are taking any of the following drugs: ACE inhibitor; potassium sparing diuretics; aspirin on a near daily basis; coumadin or other blood thinners

Patients who are taking drugs known to inhibit P450 2C9 and drugs metabolized by P450 2D6

Patients who have G6PD deficiency and those taking St. John's Wort

Unusual surgical difficulty (determined from panoramic radiograph or during the actual surgery)

Special Instructions: Currently Not Provided

Keywords:

Prostanoid

Cyclooxygenase (COX)

Selective Cox Inhibitor

Acute Peripheral Inflammation

Neuronal Expression of COX

Pain

Coxibs

Recruitment Keywords:

Wisdom Teeth

Third Molar Extraction

Third Molar Impaction

Conditions:

Healthy

Tooth Extraction

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Bazan NG. Related Articles, Links No abstract COX-2 as a multifunctional neuronal modulator. Nat Med. 2001 Apr;7(4):414-5. No abstract available. PMID: 11283664

Butte A. Related Articles, Links Abstract The use and analysis of microarray data. Nat Rev Drug Discov. 2002 Dec;1(12):951-60. Review. PMID: 12461517

Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. Related Articles, Links Free in PMC COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. PMID: 12242329

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