Bradykinin Receptors and Pain
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Tooth, Impacted
Intervention: Wisdom tooth extraction (Procedure)
Phase: Phase 2
Sponsored by: National Institute of Nursing Research (NINR)
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
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.
Official title: Bradykinin-1 Receptor and Kinin Induction in a Clinical Model of Tissue Injury
Study design: Treatment, Safety/Efficacy Study
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.
Minimum age: N/A.
Maximum age: N/A.
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
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
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
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,
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
Locations and Contacts
National Institute of Nursing Research (NINR), Bethesda, Maryland 20892, United States
Walker K, Perkins M, Dray A. Kinins and kinin receptors in the nervous system. Neurochem Int. 1995 Jan;26(1):1-16; discussion 17-26. Review.
Ahluwalia A, Perretti M. B1 receptors as a new inflammatory target. Could this B the 1? Trends Pharmacol Sci. 1999 Mar;20(3):100-4.
Bock MG, Longmore J. Bradykinin antagonists: new opportunities. Curr Opin Chem Biol. 2000 Aug;4(4):401-6. Review.
Starting date: May 2004
Ending date: February 2006
Last updated: March 3, 2008