HealthyPhase 2NCT00078104
Prostanoid Levels After Medication to Prevent Pain Following Third Molar (Wisdom Tooth) Extraction
A Phase 2 study testing Extraction of wisdom teeth in people with Healthy and Tooth Extraction, run by National Institute of Dental and Craniofacial Research (NIDCR) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Healthy, Tooth Extraction
- What is being tested?
- Extraction of wisdom teeth
- Type of treatment
- Surgery or procedure
- How many people
- 148 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2004to Oct 2005
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Show all 10Show fewer
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute of Dental And Craniofacial Research (NIDCR)
Bethesda, Maryland, 20892
About this study
Official title: Proinflammatory Gene Expression and Prostanoid Levels in a Clinical Model of Tissue Injury
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.
Read more
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.
Read the detailed description
Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal anti-inflammatory drugs. Recently, the presence of a variant of COX-1, named COX-3, has been demonstrated that is especially sensitive to acetaminophen and strongly expressed in brain tissue. The proposed study will examine prostanoid suppression in the periphery by inhibition of COX-1, -2, and -3, and evaluate the time course of expression of COX isoenzymes in terms of level of mRNA and protein itself.
Subjects (N equals 88) will be healthy volunteers scheduled for the surgical removal of impacted third molars. Using a double-blinded, randomized, parallel study design, subjects will be allocated to one of four treatment groups and will be administered a dose of blinded medication or placebo. One hour prior to oral surgery, rofecoxib 50 mg, acetaminophen 1000 mg or placebo in two groups will be administered orally. Half hour prior to surgery, ketorolac 30 mg or placebo, will be administered intravenously. Microdialysis will be performed with sample collection concurrent with pain report over the immediate postoperative period of three hours, and the collected transudate will be analyzed by ELISA to evaluate prostanoid (prostaglandin E2, thromboxane B2) production. Subjects within each group will be further randomized to have a biopsy collected at baseline prior to surgery and either at the time when a subject asks for rescue drug within 3 hours or at 24 hours following surgery. The biopsies will be frozen in liquid nitrogen and assayed later by RT-PCR for levels of COX-1, COX-2, or COX-3 mRNA, and by microarray for evaluation of change in overall mRNA expression. A portion of the biopsy samples will be immunostained to reveal the tissue-specific pattern of each COX isoenzymes expression within the inflammatory tissue, and another part of the biopsy samples will be analyzed by Western blot to quantify the amount of protein. Fifty ml of blood will be collected from all subjects, and the single nucleotide polymorphisms (SNPs) in the genes regulated by inflammatory responses such as COX-1, COX-2, PGE receptors (EPs), and microsomal PGE synthase (mPGES) genes, will be analyzed to investigate the role of genetic factors in individual differences of drug responses. The analgesic effect of the drugs will be assessed in the clinic every 20 minutes for the first three hours after extractions, and on the next morning before taking any medication using two pain intensity assessment instruments: a category scale, and a visual analog scale (VAS).
We anticipate that non-selective COX inhibitor, the selective COX-2 inhibitor, and the selective COX-3 inhibitor will differentially alter prostanoid production over the time course evaluated, and that primary sensory neurons innervating in the inflammatory tissues may differentially express COX isoenzymes that differ in sensitivity to prototypic NSAIDs, coxibs, and acetaminophen. We also anticipate that several SNPs will contribute to the individual differences in COX expression and drug responses, which has implications for individual variation in pain, analgesic responses, and neuronal plasticity.
- Conditions
- Healthy, Tooth Extraction
- Being tested
- Extraction of wisdom teeth
- Keywords
- Prostanoid, Cyclooxygenase (COX), Selective Cox Inhibitor, Acute Peripheral Inflammation, Neuronal Expression of COX, Pain, Coxibs, Wisdom Teeth, Third Molar Extraction, Third Molar Impaction
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Extraction of wisdom teethProcedure or surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Feb 2004 (estimated)
- Study startFeb 2004
- Study completionOct 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Enrolment
- 148 participants
Sponsor and investigators
- Lead sponsor
- National Institute of Dental and Craniofacial Research (NIDCR)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00078104
- Sponsor's protocol ID
- 040124
- Other IDs
- 04-D-0124
- Status last verified
- Oct 2005
- First submitted
- 18 Feb 2004
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med. 2001 Apr;7(4):414-5. doi: 10.1038/86477. No abstract available.
PubMed 11283664Butte A. The use and analysis of microarray data. Nat Rev Drug Discov. 2002 Dec;1(12):951-60. doi: 10.1038/nrd961.
PubMed 12461517Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. 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. doi: 10.1073/pnas.162468699. Epub 2002 Sep 19.
PubMed 12242329
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Proinflammatory Gene Expression and Prostanoid Levels in a Clinical Model of Tissue Injury
- ClinicalTrials.gov ID
- NCT00078104
- Acronym / sponsor ID
- 040124
- Conditions
- Healthy, Tooth Extraction
- Keywords
- Prostanoid, Cyclooxygenase (COX), Selective Cox Inhibitor, Acute Peripheral Inflammation, Neuronal Expression of COX, Pain, Coxibs, Wisdom Teeth
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 148 participants
- Lead sponsor
- National Institute of Dental and Craniofacial Research (NIDCR)US National Institutes of Health
- Study start
- Feb 2004
- Study completion
- Oct 2005
- First posted
- 19 Feb 2004 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal anti-inflammatory drugs. Recently, the presence of a variant of COX-1, named COX-3, has been demonstrated that is especially sensitive to acetaminophen and strongly expressed in brain tissue. The proposed study will examine prostanoid suppression in the periphery by inhibition of COX-1, -2, and -3, and evaluate the time course of expression of COX isoenzymes in terms of level of mRNA and protein itself.
Subjects (N equals 88) will be healthy volunteers scheduled for the surgical removal of impacted third molars. Using a double-blinded, randomized, parallel study design, subjects will be allocated to one of four treatment groups and will be administered a dose of blinded medication or placebo. One hour prior to oral surgery, rofecoxib 50 mg, acetaminophen 1000 mg or placebo in two groups will be administered orally. Half hour prior to surgery, ketorolac 30 mg or placebo, will be administered intravenously. Microdialysis will be performed with sample collection concurrent with pain report over the immediate postoperative period of three hours, and the collected transudate will be analyzed by ELISA to evaluate prostanoid (prostaglandin E2, thromboxane B2) production. Subjects within each group will be further randomized to have a biopsy collected at baseline prior to surgery and either at the time when a subject asks for rescue drug within 3 hours or at 24 hours following surgery. The biopsies will be frozen in liquid nitrogen and assayed later by RT-PCR for levels of COX-1, COX-2, or COX-3 mRNA, and by microarray for evaluation of change in overall mRNA expression. A portion of the biopsy samples will be immunostained to reveal the tissue-specific pattern of each COX isoenzymes expression within the inflammatory tissue, and another part of the biopsy samples will be analyzed by Western blot to quantify the amount of protein. Fifty ml of blood will be collected from all subjects, and the single nucleotide polymorphisms (SNPs) in the genes regulated by inflammatory responses such as COX-1, COX-2, PGE receptors (EPs), and microsomal PGE synthase (mPGES) genes, will be analyzed to investigate the role of genetic factors in individual differences of drug responses. The analgesic effect of the drugs will be assessed in the clinic every 20 minutes for the first three hours after extractions, and on the next morning before taking any medication using two pain intensity assessment instruments: a category scale, and a visual analog scale (VAS).
We anticipate that non-selective COX inhibitor, the selective COX-2 inhibitor, and the selective COX-3 inhibitor will differentially alter prostanoid production over the time course evaluated, and that primary sensory neurons innervating in the inflammatory tissues may differentially express COX isoenzymes that differ in sensitivity to prototypic NSAIDs, coxibs, and acetaminophen. We also anticipate that several SNPs will contribute to the individual differences in COX expression and drug responses, which has implications for individual variation in pain, analgesic responses, and neuronal plasticity.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Extraction of wisdom teeth | Procedure or surgery | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2008.
- Background: PubMed 11283664Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med. 2001 Apr;7(4):414-5. doi: 10.1038/86477. No abstract available.
- Background: PubMed 12461517Butte A. The use and analysis of microarray data. Nat Rev Drug Discov. 2002 Dec;1(12):951-60. doi: 10.1038/nrd961.
- Background: PubMed 12242329Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. 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. doi: 10.1073/pnas.162468699. Epub 2002 Sep 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Extraction of wisdom teeth in people with Healthy and Tooth Extraction, run by National Institute of Dental and Craniofacial Research (NIDCR) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00078104, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2008.