Single Dose Oral Celecoxib (With or Without Acetaminophen) for Acute Post-operative Pain Following Impacted Third Molar Surgery.
Phase: PHASE4
Conditions: Pain, Postoperative
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Single Dose Oral Celecoxib (With or Without Acetaminophen) for Acute Post-
operative Pain Following Impacted Third Molar Surgery. 
 
NCT04790812 
 
Version Date: 07/07/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
Protocol Title: 
Single dose oral celecoxib (with or without acetaminophen) for acute post- 
operative pain following impacted third molar surgery. 
 
Principal Investigator: 
Harry D. Gilbert, DDS 
 
Co-Investigators: 
Casandra L. Barnes, BS, Arthur Jeske, DMD, PhD., Alan L. Myers, PharmD, 
PhD, RPh, and Kimberly S. Ruona, DDS. 
 
Population: 
Approximately 100 adults (females/males) with ASA 1 and certain ASA 2 
physical status classifications requiring surgical third molar extractions. 
 
Number of Sites: 
Single site in the Oral and Maxillofacial Surgery Clinic (OMS) at the University 
of Texas School of Dentistry at Houston (UTSD) 
Study Duration: 
2 years 
 
Subject Duration: 
1 week. Subject is scheduled for third molar surgery and must document 
pain for 3 days postoperatively. 5 to 7 days later, the subject is called to 
determine if he/she needs to return for a postoperative follow-up 
appointment. 
 
 
General Information 
 
This randomized, double-blind, placebo-controlled, prospective clinical trial is designed to compare 
the postoperative pain reduction of a single agent nonsteroidal anti-inflammatory drug (NSAID) and 
NSAID combination regimen administered preemptively. Subjects will be given a single oral dose of a 
cyclooxygenase-2 (COX-2) selective inhibitor (celecoxib 200mg), or celecoxib 200 mg in combination 
with acetaminophen (APAP 1000 mg) 30 to 60 minutes prior to the procedure. Oral surgery 
involving at least one impacted mandibular third molar will be performed using a combination of 
intravenous sedation and local anesthesia following UTSD surgical protocol. All subjects will be 
released with identical postoperative instructions and prescriptions for pain management. 
Nonopioid pain management will be prescribed as follows: 600mg ibuprofen with 500 mg APAP 
every 6 hours for the first 3 days, then as needed for pain. Subjects will be asked to document 
medication consumption, postoperative pain and complications for the following 3 days using a 
Qualtrics survey. An oral and maxillofacial surgery resident or faculty on call can offer emergency 
intervention with prescription of an opioid analgesic. 
 
Background Information 
 
The need for new and improved methods of pharmacological pain management without addictive 
properties is evident as the United States confronts a surmounting opioid epidemic. According to 
the CDC, more than 70,200 deaths were caused by a drug overdose in 2017. Of these deaths, about 
68% involved an opioid and the total number of deaths in 2017 due to opioid overdose was 6 times 
higher than those seen 18 years prior. The lives of approximately 130 Americans are claimed by 
opioid overdose each day. (https://www.cdc.gov/drugoverdose/epidemic/index.html). 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
Preemptive analgesia is thought to reduce the magnitude and duration of postoperative pain by 
preventing the nociceptive sensitization caused by certain prostaglandins. While the topic of 
preemptive analgesia for dental procedures remains controversial, some studies suggest lower 
levels of pain in patients pre-medicated prior to surgery. In a study done by Bauer et al. 2013, 
preemptive ibuprofen showed no significant pain reduction following third molar surgery. However, 
when ibuprofen is combined with dexamethasone, superior postoperative pain management is 
observed.1 A number of studies have found that ibuprofen administered before surgery shows no 
significant difference in postoperative pain reduction when compared with placebo or postoperative 
administration.1,5 Even so, confounding evidence is seen in other studies and conclusive data for 
preemptive analgesia has been evasive due to differing experimental models including variations in 
the preemptive analgesic used, route of drug administration, local anesthesia and sedation during 
surgery, postoperative prescriptions, and subject selection.8 
 
NSAIDs are used ubiquitously in pain management. Even so, the potential for gastrointestinal upset 
and bleeding occurs with nonselective COX inhibitors (eg. Ibuprofen, naproxen) due to hindrance of 
the gastroprotective functions of the COX-1 enzyme.4,6 On the other hand, COX-2 selective inhibitors 
show no evidence of changes to platelets. As a result, COX-2 selective inhibitors may reduce patient 
experiences of postoperative gastrointestinal upset and perioperative bleeding. COX-2 selective 
inhibitors, such as celecoxib (Celebrex), are generally overlooked due to their connection to 
subsequent cardiovascular and cerebrovascular events when used chronically, especially with 
rofecoxib (Vioxx) which was later removed from the US market. The evidence shows some risk, 
though not excessive, for clot formation and sequelae in high risk individuals using COX-2 selective 
inhibitors for 6 months or more.4,7 However, this study aims to exclude patients who may be at risk 
for these adverse events. In addition, celecoxib will be given as only a single preemptive dose for the 
management of acute dental pain. 
 
Differences in the mechanisms of COX enzyme isoforms (COX-1 and COX-2) warrant further 
investigation of the efficacy of preemptive analgesia considering the COX selectivity of various 
NSAIDs. The COX-1 role in gastroprotective mechanisms suggests that NSAIDs with lesser COX-1 
selectivity offer a safer, more tolerable alternative to nonselective NSAIDs for acute dental pain 
management.6 The role of the COX-2 isoenzyme in pain and inflammation is observed after a painful 
stimulus elicits its synthesis of prostaglandins (PG).2,4 By reducing or inhibiting the sensitization of 
nociceptors by the prostaglandins produced by COX-2, such as PG E2, preemptive COX-2 selective 
inhibition offers a potentially better postoperative experience for patients being managed for acute 
dental pain. The expected result is a decrease in postoperative dental pain while leaving the 
gastroprotective function of COX-1 intact. 
 
Objectives 
 
The goal of this clinical trial is to explore the preemptive effect of COX-2 selective inhibitors in 
combination with APAP on acute dental pain after surgical removal of impacted third molars. With 
evidence of the efficacy of COX-2 selective inhibitors in acute dental pain management, dentists can 
potentially offer various nonopioid pain management therapies to address the opioid epidemic 
while preserving the gastrointestinal housekeeping roles of COX-1. 
 
Subjects will be given preemptive analgesics prior to undergoing impacted third molar extractions 
using a combination of intravenous sedation and local anesthesia. A survey will be given to the 
subjects for postoperative pain evaluation. Pain assessment with a visual analogue scale (VAS) at 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
predetermined times after surgery (3, 8, 12, 18, 24, 36, 48, and 72 hours) will be used as the primary 
outcome measure. Secondary outcome measures will include a verbal descriptive scale to 
supplement the VAS pain assessment and a record of any emergency analgesic consumption. 
Presence of infection and delayed healing will also be documented at the postoperative follow up 
call/appointment. 
 
Study Design 
 
This is a randomized, double-blind, placebo-controlled, prospective clinical trial comparing the 
preemptive effects of celecoxib vs. celecoxib/APAP on postoperative dental pain following impacted 
third molar surgery. 
 
Per UTSD protocol, subjects will undergo assessment, radiographic imaging, and treatment planning. 
If all inclusion criteria are met, subjects will be scheduled for third molar surgery and asked to 
document his/her postoperative experience for 3 days with a Qualtrics survey online or printed. 
Patients will also document postoperative medication consumption using a medication diary. A 
follow up phone call 3-5 days after surgery will focus on questions pertaining to pain, infection, and 
other postoperative complications. If deemed necessary by this phone call, subjects are to present 
to UTSD (OMS Clinic) for a follow up 5 to 7 days after surgery for inspection of surgical site if 
deemed necessary during the follow up phone call. Any signs of delayed healing and postoperative 
infection will be documented and treated. 
 
The survey for postoperative pain evaluation includes pain assessment with a visual analogue scale 
(VAS), which will be used as the primary outcome measure. Secondary outcome measures will 
include a verbal descriptive scale to supplement the VAS pain assessment and a record of any 
emergency analgesic consumption. These records are to be documented by the patient on the 
questionnaire at predetermined times following surgery (3, 12, 18, 24, 36, 48, and 72 hours). 
 
Study Population 
 
Approximately 100 adults presenting to UTSD with an ASA 1 and certain ASA 2 physical status 
classifications for impacted third molar extractions are to be included in the study. Both females and 
males between the ages of 18 and 45 with at least one mandibular third molar planned for 
extraction will be eligible to participate. Patients with third molars showing signs of severe 
pericoronitis will be excluded. Additionally, patients with known drug allergies to any NSAIDs, 
aspirin, acetaminophen, or sulfa drugs will be excluded.  Also, patients with cardiovascular or 
hepatic diseases will be excluded. Non-compliance with pre- and post-operative medication 
regimens will result in exclusion. 
Study Procedures 
 
Day of Surgery: Patients will present to the UTSD OMS clinic for extraction of third molars. After 
signing informed consent forms, they will be randomly administered a preemptive regimen by a 
research team member to take 30 to 60 minutes prior to scheduled procedure. Randomization will 
be achieved by use of a random number generator. The PI and other members of the research team 
will not be blinded. The administration of preemptive medications will be dispensed prior to the 
start of daily operations. The research member tasked with dispensing will not be involved with the 
administration of medications to patients on the day of surgery. Subjects will be given either a single 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
oral dose of celecoxib 200mg with a placebo (Group 1) or celecoxib 200 mg in combination with 
acetaminophen 1000 mg (Group 2). 
 
Prior to planned procedures for each day, the medication regimens (Group 1: celecoxib with placebo 
and Group 2: celecoxib with acetaminophen) will be dispensed into disposable cups labeled with a 
unique identification number for investigators to track which regimen is given to each of the 
patients. This identification number will link the regimen in the disposable cup to the Group 1 or 
Group 2 regimens. This number will be documented at time of drug administration and later used to 
identify the preemptive medication taken by each patient. The surgical procedure is not to be 
completed by any member of the research team. Intravenous sedation and local anesthetic agents 
will be documented with details about time of administration and dosage. Intravenous agents that 
may be used include midazolam, fentanyl, ketamine, and propofol. A titrated moderate sedation 
approach will be used with midazolam and fentanyl. No fixed dose can be predetermined due to 
differences in patient response to sedative medications. Ketamine and propofol may be used for 
deeper sedation as needed. General adult dosing guidelines for sedation medications will be as 
follows: 
Midazolam (Versed): 0.02- 0.1 mg/kg initially, may repeat with 25% of initial dose after 3- 5 
minutes. Not to exceed 2.5 mg per dose (1.5 mg for elderly). Not to exceed 5 mg cumulative 
dose (3.5 mg for elderly). 
 
Fentanyl: 1-2 mcg/kg with slow IV push (over 1-2 minutes), may repeat dose after 30 minutes. 
Ketamine: 1-2 mg/kg. 
Propofol: 0.5- 1 mg/kg loading dose, may repeat by 0.5 mg/kg increments every 3- 5 minutes. 
 
Local and topical anesthetics will be used at the discretion of the dental surgeon. Commonly used 
anesthetic agents are 2% Lidocaine with 1:100,000 epinephrine, 4% Articaine with 1:100,000 
epinephrine, and 0.5% Bupivacaine 1:200,000 epinephrine. Topical anesthetic used is 20% 
Benzocaine gel. Surgical procedure should not exceed 2.5 hours. 
 
Postoperative pain assessment: Subjects will be given postoperative instructions, prescriptions, 
medication diary, and a survey for documentation of pain 3 days after surgery. 
 
Postoperative follow-up: Subjects will be called 5-7 days after procedure and asked to present to 
UTSD OMS clinic if necessary. Evidence of infection or delayed wound healing will be documented 
and treated. 
 
Data and Safety Monitoring 
 
Postoperative swelling, pain, bleeding and potential infection are risks associated with any dental 
extraction. Additionally, patients may experience trismus or suffer from dry socket after the 
procedure. The OMS clinic, or an on-call OMS resident after hours, will address any issues 
concerning postoperative care that is not manageable with the instructions and analgesic regimen 
given to study subjects. Emergency intervention might include other nonopioid and/or opioid 
analgesic pharmacotherapy, addition of corticosteroids or antibiotic prescriptions, or surgical 
therapy as determined by the OMS resident. Intolerable pain should be noted by the patient and the 
resultant emergency intervention should be documented on the questionnaire. 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
 
It is possible that patients may experience allergies or other adverse drug reactions to ibuprofen, 
acetaminophen, and celecoxib during postoperative pain management. If such an event occurs, 
patient will be advised to discontinue the medications, seek immediate emergency medical 
attention in severe reactions, and document the adverse reaction. Time of event, description of 
event, and the patient response to the event should be documented on the patient survey. 
 
Statistics 
 
For each of eight increments over 72 hours, we will measure multiple response variables indicative 
of pain for the both the NSAID and NSAID/APAP combination groups. As this study involves multiple 
measures of the same individual, we will use generalized linear mixed effects model to assess the 
effect of pain killers on pain as a fixed factor and (time|individual) as a random effect. In addition, 
we will derive one index measure for the difference between the peak in pain minus the minimum 
pain to allow us to use a more simplified statistical model without a random effect, for which we will 
analyze the data using a generalized linear model with appropriate error structure. 
 
Ethics 
 
IRB approval will be sought from UTHealth Committee for the Protection of Human Subjects (CPHS) 
prior to any study procedures. 
 
Only subjects completing informed consent forms will be allowed to participate. A Spanish version 
of the consent document will be submitted after the English version has been approved. 
 
Data handling and record keeping 
 
New patient records including radiographs will be reviewed by OMS faculty (Harry Gilbert, DDS; 
Principal Investigator) and prospective participants will be selected by criteria mentioned previously. 
Subjects meeting the criteria will be invited to participate in the study before surgery. Patient name, 
DOB, telephone number, EHR number, and date of procedure will be accessed by team members of 
the study. Records for this study will be stored in a locked file cabinet within a locked office space, 
accessible only to study team members. A folder for each participant will contain PHI, panoramic 
radiographs, signed consent forms, surgical details, and survey data retrieved during this study. 
 
Publication Plan 
 
Abstract submission, poster or platform presentation, and publication in a peer-reviewed journal. 
 
References 
 
1. Bauer HC, Duarte FL, Hortiana A, et al. Assessment of preemptive analgesia with ibuprofen 
coadministered or not with dexamethasone in third molar surgery: A randomized double-blind 
controlled clinical trial. Oral and Maxillofacial Surgery 17:165, 2013. 
 
2. Cicconetti A, Bartoli A, Ripari F, and Ripari A. Cox-2 selective inhibitors: A literature review of 
analgesic efﬁcacy and safety in oral-maxillofacial surgery. Oral and Maxillofacial Surgery. 2004 
Feb; 97(2): 136-146. 

IRB NUMBER: HSC-DB-20-0118 
IRB APPROVAL DATE: 07/07/2020 
 
 
3. Gong L, Thorn CF, Bertagnolli MM, Grosser T, Altman RB, and Klein TE. Celecoxib pathways: 
pharmacokinetics and pharmacodynamics. Pharmacogenetic Genomics. 2012 April; 22(4): 310– 
318. 
 
4. Hawkey CJ. COX-1 and COX-2 inhibitors. Best Practice & Research Clinical Gastroenterology. 
2001; Vol. 15, No. 5, pp. 801-820. 
 
5. Jung Y-S, Kim M-K, Um YJ, et al. The effects on postoperative oral surgery pain by varying NSAID 
administration times: Comparison on effect of preemptive analgesia. Oral Surgery Oral Medicine 
Oral Pathology Oral radiology 100:559, 2005. 
 
6. May N, Epstein J, and Osborne B. Selective COX-2 inhibitors: A review of their therapeutic 
potential and safety in dentistry. Oral Surgery Oral Medicine Oral Pathology. 2001 Oct:92(4): 
399-405. 
 
7. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or 
Ibuprofen for Arthritis. New England Journal of Medicine. 2016 Nov: 375(26); 2519-29. 
 
8. Ong CK, Lirk P, Seymour RA, and Jenkins BJ. The efficacy of preemptive analgesia for acute 
postoperative pain management: a meta-analysis. Anesthesia and Analgesia. 2005 Mar; 
100(3):757-73.