Bradykinin Receptors and Pain
Bradykinin Receptors and Pain
This study will examine whether bradykinin receptors are produced at the site of wisdom tooth
 extraction and if they contribute to the amount of inflammation and pain that follows
 surgery. Bradykinin is a molecule produced by enzymes at the site of an injury and then binds
 to receptors to cause pain. The study will also evaluate the role of genetic factors in the
 production of bradykinin and their receptors and the pain associated with minor surgical
 procedures.

 Patients between 16 and 35 years of age who are referred to the NIH dental clinic for removal
 of two wisdom teeth may be eligible for this study. Candidates must be in good health and
 must not be allergic to aspirin, non-steroidal anti-inflammatory drugs, sulfites, or amide
 anesthetics. They will be screened with a medical history and oral examination, including
 x-rays to confirm the need for wisdom tooth extraction.

 On the morning of surgery following an overnight fast, participants have a blood sample drawn
 to extract DNA for gene studies. Just before surgery, they are given an intravenous (IV)
 sedative to induce drowsiness and a local anesthetic to numb the mouth. They are also given
 IV either Ketorolac, a non-steroidal anti-inflammatory drug, or placebo, a look-alike
 medication with no active ingredient. After the extractions, a small piece of plastic tubing
 is placed in both extraction sites, and every 20 minutes for the next 3 hours inflammatory
 fluid is collected from the tubing for measuring chemicals believed to cause pain and
 swelling. Patients rate their pain by answering pain-related questions every 20 minutes.
 Patients who have pain that is not relieved by the study medication (Ketorolac or placebo)
 are given, upon request, 50 mg of the pain reliever tramadol (Ultram). Patients remain in the
 clinic for at least 3 hours and no more than 7 hours after surgery in order for monitoring
 the effects of the study drugs as the local anesthetic wears off.

 Patients undergo two biopsies during the study - one before and one after the extraction - to
 measure any changes in chemicals produced in response to the surgery. The second biopsy is
 done either 3, 7, or 24 hours after the extraction. Patients in the 3- and 7-hour groups are
 given a small dose of local anesthetic in the gum for the second biopsy and remain in the
 clinic until the biopsy is done; those in the 24-hour group are given forms to record pain
 ratings at home and return to the clinic the following morning for a 2-hour follow-up visit.
 All patients are given standard pain medication (flurbiprofen) to take at home.
Bradykinin B1 receptors and their natural agonists are known to be rapidly induced in local
 tissues by a variety of inflammatory stimuli. Preclinical evidence, demonstrating that
 interruption of B1 receptor function causes analgesia under a variety of conditions, has been
 well established using selective antagonists and genetically modified mice. Accordingly,
 efforts are underway in several laboratories to develop novel B1 receptor antagonists as
 potential novel analgesic agents. The proposed studies will examine the kinetics of local
 induction of B1 receptors and kinin formation in a common situation of acute inflammatory
 pain in humans - tooth extraction. In addition, an examination of expression of additional
 genes of interest under these conditions using microarray analysis will be conducted.
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 a possible 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 at 3, 7 or 24 hours following surgery

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

 Must have two lower partial (rating is equal to 3) or fully impacted (rating is equal to 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 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

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