Clinical trial NCT04694300
Conditions: Osseointegrated Dental Implantation Pain, Acute
Keywords: Naproxen sodium Acetaminophen Postsurgical dental pain Prostaglandins Interleukins
Sponsor: Hersh, Elliot V., DMD, MS, PhD
Start date: 2021-02-07; Completion date: 2022-08-28
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This double-blind pilot study will evaluate the anti-inflammatory and analgesic effects of an over-the-counter (OTC) regimen of naproxen sodium versus acetaminophen in patients receiving one or two (adjacent) dental implants. It will also confirm that naproxen sodium in the OTC dosage range is a good alternative to immediate-release opioid formulations, which are subject to misuse, abuse and diversion in this patient population.

Detailed description:
Placement of dental implants is a frequently performed outpatient surgical procedure, with United States dentists currently placing implants in approximately 500,000 patients per year.This procedure has become the gold standard for replacing missing teeth due to its high level of predictability and patient acceptance, with long-term success rates greater than 95%. Thus, the number of patients opting for this procedure over dentures and fixed bridges continues to increase. In the period between 1999 and 2000 only 0.7% of the USA population had missing teeth with implants in contrast to 5.7% between 2015 and 2016 It is estimated that by 2026, if the current pace of dental implant placement continues, approximately 17% of the population will have dental implants.

Dental implant surgery involves the incision of gingival tissue to expose the underlying bone, followed by the creation of a precise bony cavity where the implant will be placed using a specialized surgical drill, and lastly the screwing of the implant into bone using a specialized handpiece Thus, it is not surprising that post-surgical pain is a common sequela following dental implant surgery. Patients often experience post-surgical pain for several days after the placement of one to three dental implants, but at a pain intensity level that is generally less than that of dental impaction surgery. This post-surgical pain is inflammatory in nature; thus, NSAIDs have demonstrated efficacy and are the preferred analgesics in this patient population. Postoperative administration of intranasal ketorolac (SPRIX®) and oral acetaminophen 325 mg plus codeine 30 mg have both demonstrated efficacy.

The soft tissue and bony trauma associated with dental implant surgery upregulates inflammatory mediators both locally and systemically. Elevated levels of interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1β have been observed in gingival crevicular fluid (GCF) from the implant site and the adjacent teeth one week after surgery. Prostaglandin E2 has been measured in the GCF of teeth surrounding implant sites employing similar methodology. Additionally, standard periodontal flap and bony recontouring surgery, which shares many similarities to dental implant surgery, induces an upregulation in immunoreactive prostaglandin E2 and leukotriene B4 levels at the surgical site. Dental implant surgery also increases cytokine levels in plasma, indicative of a systemic inflammatory response. Thus, in addition to being a model to study the efficacy and tolerability of OTC analgesics, dental implant surgery also appears to be an excellent model to study the anti-inflammatory properties of NSAIDs such as naproxen sodium.

Therefore, the investigators propose to initiate a double-blind, pilot study to evaluate the anti-inflammatory and analgesic effects of an OTC regimen of naproxen sodium versus acetaminophen in dental implant surgery patients. Notably, the vast majority of these patients are over the age of 45, a patient demographic that is rarely captured in postsurgical dental pain studies. Compared to dental impaction surgery patients, implant surgery patients possess more comorbidities such as hypertension, hyperlipidemia and hyperglycemia Thus, while dental impaction patients are typically on few if any drugs, polypharmacy is more of the norm in dental implant surgery patients. Performing a controlled study with OTC naproxen sodium in this population will provide the opportunity to confirm that its short-term use is generally safe and effective in these older, more medically complex patients. It will also confirm that naproxen sodium in the OTC dosage range is a good alternative to immediate-release opioid formulations, which are subject to misuse, abuse and diversion in this patient population.

Arms: arm 1: Naproxen sodium 440 mg followed by naproxen sodium 220 mg q 8h (max 660 mg/day) arm 2: Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert)
Interventions: intervention 1: Naproxen intervention 2: Acetaminophen intervention 3: Tramadol
Intervention descriptions: intervention 1: 440 mg by mouth immediately after completion of implant surgery followed by 220 mg 12 hours later.

Then 220 mg every 8 hours for the next two days. intervention 2: 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg. intervention 3: 50 mg by mouth every 6 hours as needed for pain

Protocol documents:
ICF_002.pdf: 
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Research Study Summary for Potential Subjects 
The research study is being conducted to learn how patients who undergo routine standard of care 
dental implant surgery respond to the approved over-the-counter pain-relieving drugs naproxen 
sodium (Aleve®) and acetaminophen (Extra Strength Tylenol®). Both of these drugs are currently 
recommended by dental implant surgeons to control pain after implant surgery and are therefore 
available to patients who do not participate in this study.  In addition to studying how well each drug 
works, we are also looking for substances in blood, urine and the fluid between your teeth and gums, 
called gingival crevicular fluid (GCF), that may correlate to how well the drug works for you. 
If you agree to join the study, you will be asked to complete the following research procedures: 
- On the day of your surgery, you will need to arrive at the Dental School at least 45 minutes before
surgery to answer some questions regarding your health and any medications you are taking and
the collection of blood, urine and GCF samples for research purposes. You will need to remain at
the Dental School for at least 6 hours after surgery for collecting these samples and for frequent
pain ratings.  So your total time at spent at the Dental School between the surgery and research
procedures will be 7 to 8 hours.
- You will take naproxen sodium, 440 mg (2 Aleve’s®), or acetaminophen, 1000 mg (2 Extra
Strength Tylenol®), right after surgery.  Your chances of getting one or the other are equal.  We
won’t know and you won’t know what you get. You could be recommended and buy either of
these pain relievers without participating in the study.
- During the 6 hours after surgery, you will be asked to give frequent pain-ratings (on a scale of 0-
10) and we will collect urine, blood and GCF samples
- At home you will continue to take naproxen sodium, 220 mg (one Aleve®), or acetaminophen
1000 mg, as instructed.  We won’t know and you won’t know what you are taking.
- At home you will record pain ratings on the day of surgery and for two days afterwards
- If your pain is not sufficiently relieved you will be allowed to take tramadol, 50 mg, a prescription
opioid that we will give you (6 pills). You could be prescribed this pain reliever without
participating in this study.   Only take the tramadol if you need it!
- You will return to the dental school at 24 hours and 72 hours after your surgery for one urine
sample, one blood sample and one GCF sample.
Your participation will last for approximately 3 to 5 days. The most common risks of participation are 
side effects of the pain-reliever drugs. The following are possible side effects of each drug. 
- Naproxen sodium: nausea, stomach pain, heartburn, dizziness, rash.
- Acetaminophen: headache, stomach ache, gas. People who take too much acetaminophen
(overdose) can injure their liver.
- Tramadol: lightheadedness, dizziness, feeling sleepy, nausea, vomiting, constipation. You cannot
drive when on tramadol. Misuse of tramadol can result in addiction and in some cases overdose
and death.
Please note that there are other factors to consider before agreeing to participate such as additional 
procedures, use of your personal information, costs, and other possible risks not discussed here. If you 
are interested in participating, a member of the study team will review the full information with you. You 
are free to decline or stop participation at any time during or after the initial consenting process. 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT AND HIPAA AUTHORIZATION FORM 
Protocol Title: 
Demonstration of OTC Naproxen Sodium’s (Aleve’s) Anti-
inflammatory Action in Dental Implant Surgery Patients 
Principal 
Investigators: 
Elliot V. Hersh DMD, MS, PhD  
Department Oral Surgery/Pharmacology  
University of Pennsylvania School of Dental Medicine 
240 South 40th Street  
Philadelphia PA 19104-6030 
Office Phone: 215-898-9686 
Katherine N. Theken PharmD, PhD 
Department Systems Pharmacology and 
Translational Therapeutics  
University of Pennsylvania 
Perelman School of Medicine 
Smilow Center for Translational Research 
10th Floor 3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Office Phone: 215-573-9592 
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Coinvestigators: 
Jonathan Korostoff, DMD, PhD 
Department of Periodontics 
Evans Building, 1st Floor 
Phone: 215-573-3965 
Joseph P. Fiorellini, DMD, DMSc 
Department of Periodontics 
Evans Building, 3rd Floor 
Phone: 215-898-3268 
Yu-Cheng Chang, DDS, MS, DMD 
Department of Periodontics 
Evans Building, 3rd Floor, East #13 
Phone: 215-573-6112 
Thomas Yoo DMD 
Departments of Periodontics and Prosthodontics 
Evans Building, 1st Floor 
Phone: 646-532-1500 
Emergency 
Contact: 
Stacey Secreto CCRC – Research Coordinator 
Office Phone: 215-746-8891 
Cell Phone: 484-354-4442 
After Hours: 215-868-7984. Ask for Periodontist on call 
You are being invited to participate in a research study. Your participation is voluntary, and you 
should only participate if you completely understand what the study requires and what the risks 
of participation are. You should ask the study team any questions you have related to 
participating before agreeing to join the study. If you have any questions about your rights as a 
human research participant at any time before, during or after participation, please contact the 
Institutional Review Board (IRB) at (215) 898-2614 for assistance. 
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you are an adult who 
requires the surgical placement of one or two dental implant screws and teeth to 
replace a tooth or teeth that you lost in either your bottom or top jaw, and we expect you 
will need some pain relievers after surgery. The surgery is the standard of care that you 
would be receiving whether you participated in the study or not, and the risks and 
benefits of the surgery will be explained by your periodontist.  Your participation is 
voluntary which means you can choose whether or not you want to participate. If you 
choose not to participate, there will be no loss of benefits to which you are otherwise 
entitled. Before you can make your decision, you will need to know what the study is 
about, the possible risks and benefits of being in this study, and what you will have to 
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do in this study. The research team is going to talk to you about the research study, and 
they will give you this consent form to read. You may also decide to discuss it with your 
family, friends, or family doctor and dentist. You may find some of the medical language 
difficult to understand. Please ask one of the study doctors and/or the research 
coordinator about this form. If you decide to participate, you will be asked to sign this  
form. 
What is the purpose of this research study? 
Patients who have dental implant surgery usually experience some pain that may last 
for 2 or 3 days after the procedure, and over-the-counter (OTC) pain relievers such as 
naproxen sodium (Aleve®), acetaminophen (Tylenol® ES) or ibuprofen (Advil®) are  
usually recommended by their periodontal surgeons.  A few people may experience 
pain that is severe enough to require a prescription opioid such as hydrocodone in 
Vicodin® or tramadol in Ultram® as well as OTC pain relievers.  
The purpose of this study is to compare the effects of OTC naproxen sodium, 440 mg (2 
Aleve®), followed by 220 mg once every 8 hours for 3 days to the effects of 
acetaminophen, 1000 mg (2 Tylenol® Extra Strength), taken three times per day for 3 
days. We will evaluate how well the two drugs relieve pain and whether they reduce the 
amount of substances in your blood, urine and gums (gingiva) near the implants that are 
known to cause pain.  The drug that you receive will be determined solely by 
chance and you or your periodontist will not choose what medication you 
receive. 
How long will I be in the study? How many other people will be in the 
study? 
Your participation in this study will last approximately 3 days. The entire study should 
be completed in about 18 months. A total of 35 subjects will participate in this study, 
all being enrolled at the University of Pennsylvania. 
What am I being asked to do? 
The study is divided into three visits, all at the University of Pennsylvania School of 
Dental Medicine located at 240 South 40th Street in Philadelphia. You will be invited to 
participate in the study only if your treating periodontist is a member of the research 
team who has scheduled you for implant surgery, believes you can safely participate in 
the study, and has given the research team permission to talk to you either in person 
during one of your routine periodontal clinic visits or by phone. If you express interest in 
participating we tell you what the study is about and what is expected of you as a study 
participant.  We will ask you several questions about your overall health, any medication 
or substance intake (including medically approved or recreational use of marijuana, for 
example) and your experience (good and bad) with pain relievers. Patients who are 
smokers or have recently taken marijuana or other recreational drugs will be excluded 
from the study.  
Before you are enrolled in the study, you will be asked to read and sign this informed 
consent. You will have time to discuss it with family, friends, or other doctors before 
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signing it, and no research procedures will be done until then.   
On the Day of Surgery (Visit #1) the following procedures will be performed: 
1. All females of child-bearing potential will have a urine pregnancy test performed. The
results of this test must be negative for continued study participation. This is
done solely for research purposes.
In addition, all potential subjects will undergo a urine drug screen for potential drugs of
abuse or drugs that can interfere with study results such as codeine (in Tylenol #3),
oxycodone (in Percocet), marijuana, benzodiazepines (like Valium), cocaine, other
stimulants (amphetamines) or nicotine. You must test negative for these drugs for
continued study participation. This is done solely for research purposes.
2. We will then stick a needle connected to a catheter (small plastic tube) into a vein in
your arm that will be used to collect blood samples immediately before surgery and at
multiple points after surgery. These samples are only for research purposes, and the
total amount of blood drawn on this day will be 4 tablespoons (60 ml). Samples
will be taken immediately before surgery, after the surgery is done but before you take
the study pain medication, and at one hour, two hours, 4 hours and 6 hours after you
take the study pain medication. We will keep the catheter in your vein, so we don’t
have to stick you with the needle again (although being stuck again with a needle again
is possible if the tube becomes clogged and we can’t get any blood from it). These
blood samples will be analyzed for the amount of certain chemicals in your blood that
may change with how much pain you experience.
3. At the same time a blood sample is drawn, we will also ask you to provide a urine
sample for research purposes, so we can look at certain chemicals in your urine that
may correlate with your pain level and with how well the pain reliever is working.
4. Right after the blood sample is drawn, we will also place thin cardboard strips between
your teeth and gums near the implants, a painless procedure to collect GCF for
research purposes.  The results of these blood, urine and GCF tests won’t be
available until several months after the study is completed and will have no
impact on your treatment and care.
5. Your implant surgery will be performed by one of the attending periodontal surgeons
using accepted standards of care (not for research purposes but for your routine
care as if you were not on the study), including the use of injected numbing
medications (2% lidocaine with epinephrine and/or 3% mepivacaine) so you don’t feel
pain during surgery, and additionally the use of nitrous oxide plus oxygen (laughing gas)
if you need it to relax. You and/or your insurance company are responsible for the
costs of the surgery, the numbing medication and the laughing gas.
6. Once the surgery is complete and you are feeling comfortable, we will move you to
the Clinical Research Center on the third floor of the Dental School in the adjoining
building called the Schattner Center. You will receive a dose of naproxen sodium,440
mg (2 Aleve®), or acetaminophen 1000 mg (2 Tylenol® Extra Strength), by mouth with
8 ounces of water for research purposes. You will probably still be numb and pain free
when you take the study pain medication. Your chances of getting either drug is one in
two, or fifty-fifty.  The study medication that you will receive will be determined solely by
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chance (like a flip of a coin). All study medications will look exactly alike so neither you, 
nor the study doctors or the research coordinator will know what you are receiving. 
However, this information can be obtained in the case of an emergency.  
7. After administering the study medication, we will ask you to report the amount of pain
you are having every 20 minutes for 6 hours. During this 6-hour in-house evaluation
period we will also ask you about any bad effects (side effects) you think the
medication has given you.  The responses you provide us are solely for research
purposes.
8. You will be encouraged to allow at least 60 minutes for the study pain medication to
work before taking any additional pain relievers, but if you start experiencing pain which
is too uncomfortable, you will receive a dose of tramadol, 50 mg. Tramadol is an opioid
(narcotic) and if misused is potentially addicting. We will supply it in a dispenser
containing six 50 mg tablets so we can easily count how many you need during the
entire course of the study. If you take one while in the research unit, five will be left for
you to take home.
9.
At 6 hours (while you are still at the Dental School), you will take your second dose of
study medication.  If you are in the acetaminophen group, you will receive
acetaminophen, 1000 mg (two Tylenol® Extra Strength).  If you are in the naproxen
group, your medication will be two placebo look-alike pills which contain no pain
medication. We are doing this because your second dose of naproxen sodium (Aleve®)
should not be taken for another 6 hours and you and the study team should not know
what you are taking. This again is being done for research purposes.
10. After you take this dose of study medication, we will give you a specialized cardboard
and plastic dispenser, a blister pack, containing your study medication and instructions
how and when to take it.  Some pills in your blister pack may be placebos, so that all
study medication looks alike and you and the study team remain unaware of what
you are taking. All this is being done for research purposes.
11. Once you understand how to use the blister pack, you will then be scheduled for your
24- hour postsurgical visit (Visit #2) back in the dental school and will be permitted to
go home. The total amount of time you will be at Penn on the day of your surgery will
be approximately 7 to 8 hours.  The research coordinator or other research personnel
will contact you by phone or text message the night after surgery to see how you are
doing and ask you a few questions about how much pain you are experiencing. It is
important to realize that while there are placebo pills in this study, everyone in
the study will be taking either 660 mg of naproxen sodium (3 Aleve®) a day or
3000 mg of acetaminophen (6 Tylenol® Extra Strength) per day for the three days
of the study. This is the maximum approved recommended dose for each drug.
In other words, everyone will be getting what is considered a good dose of pain
medication and nobody will just be taking placebos that don’t contain any pain
medication.
When taking the study medication at home: 
1. You will follow the instructions on the blister pack.  Basically, on the day of surgery
you will take a dose (two capsules of study medication) 6 hours after you leave the
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Dental School. 
2. On the first day and second day after surgery, you will take two capsules of study
medication upon awakening and 6, 8, 12 and 16 hours later. You will take the study
medication whether or not you are experiencing pain because one of the study goals
is to try to prevent pain.
3. In case you have pain that becomes very uncomfortable, you will be allowed to take
one of the tramadol pills, but no more than one every 6 hours. Do not take any
tramadol if you don’t need it. You will be given a study medication log to use in
recording the time you take each dose of study medication in the blister pack and
how much pain you were experiencing before dosing. You will also record if and
when you took any tramadol.  You should bring the blister pack, the tramadol
dispenser and the medication log sheets back with you to the 24-hour and 72-hour
study visits. While all the drugs you are taking at home are FDA approved, the
drug you are assigned to and when you are taking it is solely for research
purposes.
Visit #2, the 24-hour Postsurgical Visit, will take place in the Clinical Research Unit 
located on the third floor of the Dental School’s Schattner Building (where you were the 
day before).  
1. We will check the blister pack to see if you took the study medication as directed and
also count how many tramadol tablets are left. We will ask you at this time how much
pain you experienced at home and how well you think the study medication worked
for you.
2. We will then collect a urine sample, a blood sample (2 teaspoons) from a needle
placed in a vein in your arm and a GCF sample using the cardboard strips placed
between your gums and teeth. We will again be analyzing chemicals in the three
fluids to see if they can help us predict how much pain patients will experience and
how well the pain relievers work. The total amount of time for this visit will be
approximately 30 minutes. You will then be scheduled for Visit #3, the Final Study
Visit.  This will take place two days later (or 72 hours after your surgery).
Visit #3, the Final Study Visit, will take place approximately three days after your 
surgery at the Clinical Research Unit on the third floor of the Schattner Building.   
1. All the same things that were done at Visit #2 (counting how many pills you used,
asking you about your pain, and collecting urine, blood and GCF samples) will be
performed at this visit. We will also take back any unused medication from you. This
visit will last approximately 30 minutes. This will complete your study participation.
2. The total amount of blood taken in this study will be approximately 5.5 tablespoons
(80 ml).
What are the possible risks or discomforts? 
Naproxen sodium (Aleve®) is an over-the-counter and prescription pain reliever approved 
by the FDA. It is generally well tolerated in the short amount of time you would be receiving 
it during this study. Naproxen sodium can cause stomach bleeding and allergic reactions. 
Allergic reactions can occur with even the low doses of naproxen sodium that we 
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are studying so if you have a history of allergies to naproxen sodium (Aleve®, 
Anaprox®) ibuprofen (Advil®, Motrin®), ketorolac (Toradol®, SPRIX®), aspirin or 
other nonsteroidal anti-inflammatory drugs (NSAIDs), or if you have had an asthmatic 
attack while taking any of these drugs, you should not be in this study.  In addition, 
administering drugs like naproxen sodium shortly before or after heart surgery can cause 
unwanted complications, so if you are scheduled to have heart surgery or have had heart 
surgery within 6 months of this study, you will not be allowed to participate.      
Acetaminophen is also an FDA-approved over-the-counter pain reliever. The most 
common side effects of acetaminophen include headache, stomach ache and gas. 
People who take too much acetaminophen (overdose) can injure their liver. Therefore, it 
is important to follow the instructions that we give you for taking study medication.  The 
daily amount of acetaminophen you would be taking in this study is six 500 mg tablets, or 
a total of 3000 mg, which is below the FDA's maximum recommended daily dose of eight 
500 mg tablets (4000 mg).  Acetaminophen can also cause serious allergic reactions, so 
if you are allergic to any Tylenol® product or any product that contains 
acetaminophen, you should not be in this study. 
Tramadol is an FDA-approved prescription opioid pain reliever. The most frequently 
reported adverse reactions to tramadol are lightheadedness, dizziness, feeling sleepy, 
nausea, vomiting and constipation. Other effects reported with tramadol include difficulty 
passing urine, mood changes (both bad and good), and skin rash. If you need to take 
tramadol during this study, you should not drive a car or operate heavy machinery 
because your ability to do these tasks may be impaired. Tramadol may cause serious 
side effects in people on antidepressant medicines. Therefore, if you are on one of these 
drugs, you will not be allowed to participate in the study.  Drugs that contain tramadol 
have abuse potential, such as people using the drugs to get high or trying to sell 
them on the street. People who misuse drugs like tramadol can become addicted 
and in some cases overdose and stop breathing or have seizures. Therefore, it is 
imperative that you use the tramadol exactly as you are instructed in this study, 
and that you keep all your study medication in a secure place where other people 
will not have access to it. Any unused tramadol must be brought back to us during 
your final visit. 
The risks associated with drawing blood samples from your vein include pain and bruising 
at the needle insertion site, feeling faint and, rarely, nerve damage or infection. The 
research coordinator who performs this is highly trained at taking blood from veins. 
Your blood or other specimens will not be sold to any person, institution, or company for 
financial gain or commercial profit. Neither you nor your heirs will gain financially from 
discoveries made using the information and/or specimens that you provide.  Your blood 
will not be used for whole genome sequencing.  All measurements done with your blood 
and other specimens are for research purposes only, and you will not be informed of the 
results of the research performed on your samples. Reports about research done with 
your samples will not be given to you or your doctor. These reports will not be put in your 
health records; however, the results of this research may be used in reports and research 
publications. The investigators do not wish to identify you in connection with this research 
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and will use procedures designed to prevent the results of this research from being linked 
to you. For example, a study ID number will be used to identify the tubes that contain your 
samples, and the label will not include your name or other health information. If your 
samples or other health information are used in reports and research publications, you 
will not be identified by name, address, or phone number.
Reproductive risks: Because of unknown effects of naproxen sodium, acetaminophen 
and tramadol, there could be serious harm to unborn children or children who are breast-
feeding. These effects could also harm the mother. In addition, implant surgery is never 
performed on pregnant women because the risks of surgery and the surgical numbing 
regimens outweigh any benefit. It is also possible that harmful side effects that are not yet 
known could happen to both the mother and to the unborn or breast-feeding child from 
both the surgery and the study drugs. If you are currently pregnant, you will not be able 
participate in the study. If you are a woman who is able to become pregnant, you will be 
given a urine pregnancy test at the beginning of Visit #1 (Surgical Visit). You are asked 
to use a medically accepted method of birth control (such as abstinence, birth control pills, 
birth control shot [Depo-Provera injection], progestin implant, condoms with spermicide, 
diaphragm, cervical cap, intrauterine device [IUD], surgical methods of birth control) while 
you participate in the study. You should not become pregnant while you are taking part in 
this study. If you do become pregnant, you must tell the investigator and consult an 
obstetrician or maternal- fetal specialist. 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to 
you. This includes information that, once learned, might cause you to change your mind 
about being in the study. We will notify you as soon as possible if such information 
becomes available. 
What are the possible benefits of the study? 
You are not expected to get any direct benefit from being in this research study. 
The results of this study may help researchers gain a better understanding of managing 
pain in patients undergoing dental surgery and how well patients will respond to 
naproxen sodium and other pain relievers. 
What other choices do I have if I do not participate? 
The alternative to participating in this study is not to participate. If you do not participate, 
you would receive your dental implant surgery and be prescribed an FDA-approved pain 
reliever such as an NSAID like ibuprofen (Advil®, Motrin®), naproxen sodium (Aleve®, 
Anaprox®), acetaminophen (Tylenol® Extra Strength) or acetaminophen/hydrocodone 
(Vicodin®).  If you choose not to participate in the study, this decision will have no 
impact on the care that you would receive at the University of Pennsylvania School of 
Dental Medicine. If you are an employee or student at the University of Pennsylvania, 
participating or not participating in this study will not enhance or detract from your career 
or class standing. 
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Will I be paid for being in this study? 
You will be compensated in the following manner for your time spent in the study. 
•
Visit #1 Surgical Visit - $150
•
Visit #2, 24-hour postoperative visit - $125
•
Visit #3, 72 Hour Post-Surgical Visit - $125
•
Total Compensation - $400
Please note that if you receive more than $600.00 compensation in one year for 
participation in research studies at the University of Pennsylvania, the University will 
report this income to the Internal Revenue Service. 
Will I have to pay for anything? 
You or your insurance company will be billed for the costs of the dental implant 
surgery, including presurgical X-Rays or nitrous oxide if you need it. The cost of the 
study medications will be paid for by the study. You and/or your health insurance may 
be billed for the costs of medical care during this study if these expenses would have 
happened even if you were not in the study, or if your insurance agrees in advance to 
pay. 
What happens if I am injured from being in the study? 
In the event of any physical injury resulting from research procedures, medical 
treatment will be provided without cost to you, but financial compensation is not 
otherwise available from the University of Pennsylvania. If you wish further information 
or think something unusual has occurred because of your participation in the study, you 
should contact the Principal Investigator, Dr. Hersh, listed on the first page of this 
consent form. You may also contact the School of Dental Medicine’s Clinical 
Pharmacology Research Unit at 215-746-8871 and ask for Stacey. And you may call 
the After Hours number listed on the first page and ask for the periodontist on call. 
When is the Study over? Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all 
information has been collected. This study may also be stopped at any time by your study 
doctor, the study Sponsor, or the Food and Drug Administration (FDA) without your 
consent because: 
•
The Primary Investigator feels it is necessary for your health or safety.
Such an action would not require your consent, but you will be informed
if such a decision is made and the reason for this decision.
•
You have not followed study instructions.
•
The Sponsor, the study Principal Investigator, or the FDA has
decided to stop the study.
If you decide to participate, you are free to leave the study at any time. Withdrawal will 
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Version 07/24/2022 
 
11 of 14 
not interfere with your future care at the University of Pennsylvania. 
Who can see or use my information? How will my personal 
information be protected? 
We will do our best to make sure that the personal information in your medical record will 
be kept private. However, we cannot guarantee total privacy. Your personal information 
may be given out if required by law. If information from this study is published or presented 
at scientific meetings, your name and other personal information will not be used. If this 
study is being overseen by a clinical research monitor (someone who reviews the accuracy 
of study documents), they may review your research records. 
What information about me may be collected, used or shared with 
others? 
The following personal health information will be collected, used for research, and may 
be disclosed during your involvement with this research study: 
•
Name, address, telephone
number, date of birth
•
Social Security number
•
Personal and family medical
history
•
Current and past medications or
therapies
•
Any bad effects from study pain
relievers
•
Information from a physical examination
that generally also includes blood
pressure readings, and heart rate
•
For females, results of a urine pregnancy
test
•
Results from pain
questionnaires
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your health 
information and results of tests and procedures are used to: 
• do the research
• oversee the research
• to see if the research was done right.
Who may use and share information about me? 
The following individuals may use or share your information for this research study: 
•
The Principal Investigator and the Investigator’s study team
•
The University of Pennsylvania Institutional Review Boards (the committees
charged with overseeing research on human subjects) and University of
Pennsylvania Office of Regulatory Affairs
•
The University of Pennsylvania Office of Clinical Research (the office which
monitors research studies)
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Version 07/24/2022 
 
12 of 14 
•
Authorized members of the workforce of the University of Pennsylvania School of
Dental Medicine and University of Pennsylvania support offices, who may need to
access your information in the performance of their duties (for example: for
research oversight and monitoring, to provide treatment, to manage accounting or
billing matters, etc.).
•
Other research personnel with access to the databases for research and/or study
coordination and as otherwise approved by the University of Pennsylvania
Institutional Review Boards.
Who, outside of the Hospital of the University of Pennsylvania, might 
receive my information? 
Oversight organizations 
•
The Food and Drug Administration
•
The Office of Human Research Protections
Once your personal health information is disclosed to others outside the University of 
Pennsylvania School of Dental Medicine, it may no longer be covered by federal privacy 
protection regulations. 
The Principal Investigator or study staff will inform you if there are any additions to the list 
above during your active participation in the trial. Any additions will be subject to 
University of Pennsylvania procedures developed to protect your privacy. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
How long may the University of Pennsylvania School of Dental 
Medicine use or disclose my personal health information? 
Your authorization for use of your personal health information for this specific study does 
not expire. 
Your information may be held in a research database. However, the University of 
Pennsylvania may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
•
You have given written authorization
•
The University of Pennsylvania’s Institutional Review Board grants permission
•
As permitted by law
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the principal investigator 
for the study. If you withdraw your permission, you will not be able to stay in this study. 
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Version 07/24/2022 
 
13 of 14 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
By signing this document, you are permitting the Department of Periodontics to use and 
disclose personal health information collected about you for research purposes as 
described above. 
What may happen to my information and samples collected on this 
study? 
Your information and samples will be de-identified, meaning that all identifiers linking 
them to you have been removed. The information and samples could be stored and 
shared for future research in this de-identified fashion. It would not be possible for 
future researchers to identify you as we would not share any identifiable information 
about you with future researchers. This can be done without again seeking your 
consent in the future, as permitted by law. The future use of your information and 
samples only applies to the information and samples collected on this study. 
Electronic Medical Records and Research Results 
What is an Electronic Medical Record and/or a Clinical Trial Management 
System? 
An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record. 
A clinical trial management system (CTMS) is used to register your information as a 
participant in a study and to allow for your research data to be entered/stored for the 
purposes of data analysis and any other required activity for the purpose of the conduct 
of the research. 
If you are receiving care or have received care within the University of Pennsylvania 
School of Dental Medicine and are participating in a University of Pennsylvania 
research study, information related to your participation in the research (i.e. 
laboratory tests, imaging studies and clinical procedures) may be placed in your 
existing EMR maintained by the dental school. Information related to your 
participation in clinical research will also be contained in the CTMS. 
If you have never received care at PENN Dental Medicine and are participating in a 
University of Pennsylvania research study that uses the dental school’s service, an 
EMR will be created for you for the purpose of maintaining any information produced 
from your participation in this research study. The creation of this EMR is required for 
your participation in this study. 
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Version 07/24/2022 
 
14 of 14 
In order to create your EMR, the study team will need to obtain basic information about 
you that would be similar to the information you would provide the first time you visit a 
hospital or medical facility (i.e. your name, the name of your primary doctor, the type of 
insurance you have). Information related to your participation in the study (i.e. laboratory 
tests, imaging studies and clinical procedures) may be placed in this EMR. 
Once placed in your EMR or in the CTMS, your information may be accessible to 
appropriate UPHS workforce members that are not part of the research team. 
Information within your EMR may also be shared with others who are determined by 
the University of Pennsylvania School of Dental Medicine to be appropriate to have 
access to your EMR (e.g. Health Insurance Company, disability provider, etc.). 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this research 
study or if you have any questions about your rights as a research subject, you should 
speak with the Principal Investigator listed on page one of this form. If a member of the 
research team cannot be reached or you want to talk to someone other than those 
working on the study, you may contact the Office of Regulatory Affairs with any question, 
concerns or complaints at the University of Pennsylvania by calling (215) 898-2614. 
A copy of this consent form will be given to you. 
Name of Subject (Please Print)      Signature of Subject 
Date 
Name of Person Obtaining 
Signature 
Date 
Consent (Please Print) 
When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer. Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of this 
study. 
IRB Approved From: 08-05-2022 To: 12-06-2022

Prot_SAP_000.pdf: 
Demonstration of OTC Naproxen Sodium’s (Aleve’s) Anti-inflammatory Action in Dental Implant 
Surgery Patients 
 
 
Coprincipal investigators:  Elliot V Hersh DMD, MS, PhD    
 
 
 
 
Katherine N Theken PharmD, PhD 
Coinvestigators: Jonathan Korostoff DMD, PhD, Joseph Fiorellini DMD, DScD, Yu-Cheng 
Chang DMD, MS, Thomas Yoo DMD, Claire Mitchell PhD, Matthew C Hutcheson MS 
DATE:   06/01/2021 
 
MODIFICATION DATE TO INCREASE ENROLLMENT: 07/23/2022 
 
 


Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line agents in 
managing pain following outpatient dental procedures due to their effectiveness and lack of 
addictive potential.1,2  Naproxen sodium is widely used due to its rapid onset3 and long duration 
of action.4,5  While several studies have demonstrated the analgesic efficacy of naproxen 
sodium following third molar surgery,4,5 the effect of naproxen sodium on postoperative levels of 
inflammatory cytokines has not been examined to date.  Therefore, the aim of this research 
proposal is to evaluate the local and systemic anti-inflammatory effect of over-the-counter 
(OTC) doses of naproxen sodium following the placement of dental implants.6  As a secondary 
endpoint this study will also compare the effectiveness of naproxen sodium and acetaminophen 
in delaying and reducing postoperative pain.  
Background 
Naproxen is a member of the propionic acid group of nonsteroidal antiinflammatory 
drugs and possesses analgesic, antiinflammatory and antipyretic properties.7 The sodium salt of 
naproxen was developed as a more rapidly absorbed formulation of the drug,3 where a rapid 
onset is particularly desirable such as treating acute pain.    Prescription dosing of naproxen 
(Naprosyn®) and naproxen sodium (Anaprox®) is currently FDA-approved for a variety of 
chronic and acute inflammatory conditions including the relief of the signs and symptoms of 
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, polyarticular idiopathic juvenile 
arthritis, tendonitis and acute gout.  Both formulations are also approved for the management of 
pain and primary dysmenorrhea.7  When treating arthritic conditions, the maximum daily dose of 
prescription naproxen and naproxen sodium should not exceed 1000 mg and 1100 mg per day 
respectively.  For bursitis, tendonitis, gout, pain and dysmenorrhea the initial daily dose can be 
slightly higher; 1250 mg per day for naproxen and 1375 mg per day for naproxen sodium.7 
 
Naproxen sodium (Aleve®) is also marketed as 220 mg tablets, caplets and liquigels for 
over-the-counter (OTC) usage with a maximal daily dose not to exceed 660 mg.8 It is indicated 
for temporary relief of minor aches and pains associated with arthritis, backache, headache, the 
common cold, muscular aches, menstrual cramps and toothache.  It is also indicated for the 


temporary reduction of fever.  For the first dose, two tablets (440 mg) may be taken.8 In a 
placebo-controlled trial of acute postsurgical pain following the removal of impacted third molar 
teeth, an initial 440 mg dose of naproxen sodium was highly effective, demonstrating greater 
peak analgesic effects and a longer duration of action than acetaminophen 1000 mg (2 
Tylenol® Extra-Strength).5 A recently published study employing the same pain model also 
demonstrated that naproxen sodium 440 mg possesses equivalent peak analgesic effects but a 
longer duration of analgesic action than ibuprofen 400 mg.4  
 
Placement of dental implants is a frequently performed outpatient surgical procedure, 
with United States dentists currently placing implants in approximately 500,000 patients per 
year.6,9 This procedure has become the gold standard for replacing missing teeth due to its high 
level of predictability and patient acceptance, with long-term success rates greater than 95%.10-
12 Thus, the number of patients opting for this procedure over dentures and fixed bridges 
continues to increase.13 In the period between 1999 and 2000 only 0.7% of the USA population 
had replaced missing teeth with implants in contrast to 5.7% between 2015 and 2016.  It is 
estimated that by 2026, if the current pace of dental implant placement continues, approximately 
17% of the population will have dental implants.13  
 
Dental implant surgery involves the incision of gingival tissue to expose the underlying 
bone, followed by the creation of a precise bony cavity where the implant will be placed using a 
specialized surgical drill, and lastly the screwing of the implant into bone using a specialized 
handpiece.6  Thus, it is not surprising that post-surgical pain is a common sequela following 
dental implant surgery.14-18  Patients often experience post-surgical pain for several days after 
the placement of one to three dental implants,14,18  but at a pain intensity level that is generally 
less than that of dental impaction surgery.   This post-surgical pain is inflammatory in nature; 
thus, NSAIDs have demonstrated efficacy and are the preferred analgesics in this patient 
population.  Postoperative administration of intranasal ketorolac (SPRIX®) and oral 
acetaminophen 325 mg plus codeine 30 mg have both demonstrated efficacy.14,18   
 


 
The soft tissue and bony trauma associated with dental implant surgery upregulates 
inflammatory mediators both locally and systemically.  Elevated levels of interleukin (IL)-6, IL-8, 
and macrophage inflammatory protein (MIP)-1β have been observed in gingival crevicular fluid 
(GCF) from the implant site and the adjacent teeth one week after surgery.19 Prostaglandin E2 
has been measured in the GCF of teeth surrounding implant sites employing similar 
methodology.20  Additionally, standard periodontal flap and bony recontouring surgery, which 
shares many similarities to dental implant surgery, induces an upregulation in immunoreactive 
prostaglandin E2 and leukotriene B4 levels at the surgical site.21  Dental implant surgery also 
increases cytokine levels in plasma, indicative of a systemic inflammatory response.22,23 Thus, 
in addition to being a model to study the efficacy and tolerability of OTC analgesics, dental 
implant surgery also appears to be an excellent model to study the anti-inflammatory properties 
of NSAIDs such as naproxen sodium.   
 
Therefore, we propose to initiate a double-blind, pilot study to evaluate the anti-
inflammatory and analgesic effects of an OTC regimen of naproxen sodium versus 
acetaminophen in dental implant surgery patients.  Notably, the vast majority of these patients 
are over the age of 45,13 a patient demographic that is rarely captured in postsurgical dental 
pain studies.  Compared to dental impaction surgery patients, implant surgery patients possess 
more comorbidities such as hypertension, hyperlipidemia and hyperglycemia.24  Thus, while 
dental impaction patients are typically on few if any drugs, polypharmacy is more of the norm in 
dental implant surgery patients.24  Performing a placebo-controlled study with OTC naproxen 
sodium in this population will provide the opportunity to confirm that its short-term use is 
generally safe and effective in these older, more medically complex patients. It will also confirm 
that naproxen sodium in the OTC dosage range is a good alternative to immediate-release 
opioid formulations, which are subject to misuse, abuse and diversion in this patient 
population.1,2   
 
 


Objectives  
 
This is a 3-day, randomized, double-blind, parallel-group, single-center study in patients 
following dental implant surgery.  The primary objective of this study is to determine whether 
administration of naproxen sodium reduces levels of local and systemic inflammatory 
biomarkers, including PGE2, IL-6, and tumor necrosis factor (TNF)-α, over the initial 72 hours 
after surgery. 
 
The secondary objectives are 1) to determine whether administration of naproxen 
sodium (440 mg) compared to acetaminophen (1000 mg) immediately after surgery delays the 
onset of postoperative pain as determined by the time to first use of rescue medication over 12 
hours, and 2) to compare the effectiveness of naproxen sodium (220 mg q8h) to acetaminophen 
(1000 mg q6h for three dosing intervals) in reducing postoperative pain over the first 24 hours 
after surgery as determined by summed pain intensity scores and use of rescue medication 
(tramadol 50 mg).  
 
Further objectives of this investigation are to assess pain intensity, use of rescue 
medication and levels of inflammatory biomarkers at individual time points.   
  
Study Design 
This will be a pilot study in adult patients receiving one or two) dental implants.  Subjects 
having either maxillary and mandibular implant surgery, including those requiring extraction of a 
tooth to place the implant or bone grafting on the day of surgery, will be included.  The surgery 
as previously described involves the administration of local anesthesia (lidocaine plus 
epinephrine and/or 3% mepivacaine plain), laying a flap, creating a precise bony cavity with a 
specialized drill to receive the implant and “screwing in” the implant with another specialized 
instrument.  
 
Patients will be excluded if they have:  
 
Advanced periodontal disease (>20% Clinical Attachment Loss + >20% 
radiographic bone loss). 


 
History of bisphosphonate usage  
 
Medical history or medical condition that makes any of the study 
medications (naproxen sodium, acetaminophen, tramadol, etc.) 
inappropriate treatment options including any scheduled or recent cardiac 
procedures (within 6 months) 
 
History of asthma, urticaria or allergic-type/ hypersensitivity reactions 
after taking aspirin or other NSAIDs 
 
History of, or active gastrointestinal perforation, ulcer or bleeding related 
to previous NSAID use 
 
Severe heart failure 
 
Contraindication to opioid use 
 
Positive urine drug screen for drugs of abuse unless on stable doses of a 
non-analgesic drug for a legitimate medical purpose 
 
Pregnancy – A urine pregnancy test will be performed immediately before 
the scheduled surgery on all women of child-bearing potential 
 
Local or systemic diseases that affects wound healing and inflammatory 
biomarkers (diabetes, autoimmune (rheumatoid arthritis), or inflammatory 
disorders – osteoarthritis is allowed). 
 
Smokers on this pilot study because it can affect levels of inflammatory 
biomarkers – a urine cotinine test will be performed immediately prior to 
the scheduled surgery on all subjects even if they deny smoking history 
 
History of systemic steroid use over 2 weeks within last 2 years. 
 
Poor oral hygiene on a non-compliant individual. 
 
Anticoagulant therapy 
 
Antidepressant therapy 
 
All patients will provide informed consent prior to any study-related procedure.  Baseline 
blood, urine, and GCF samples will be collected prior to implant surgery (T=baseline) for 


assessment of COX pathway activity ex vivo and in vivo, plasma cytokine (IL-6, TNF-α) levels, 
and GCF PGE2 and cytokine levels.  Baseline COX-1 and COX-2 activity will be assessed ex 
vivo using whole blood assays as previously described.25,26  Urine will be collected to measure 
COX activity in vivo by quantification of urinary prostanoid metabolites by liquid 
chromatography/mass spectrometry as previously described.27  GCF samples will be collected 
by inserting a paper filter strip (Periopaper, Proflow, Amitville NY) into the gingival crevice of the 
teeth surrounding the implant site at three sites (distal, facial and lingual/palatal).20 For two non-
adjacent implants, one surgical site will be chosen for GCF collection. 
 
Surgery will then be performed according to the standard of care in the PENN Dental 
Medicine Periodontics Clinic with lidocaine plus 1:100,000 and/or 1:50,000 epinephrine, and/or 
3% mepivacaine plain.  Nitrous oxide sedation will be allowed.  Prohibited medication during or 
following surgery will be the use of glucocorticoids or the long-acting local anesthetic 
bupivacaine plus 1:200,000 epinephrine.  
 
After completion of the surgery, additional blood, urine, and GCF samples will be 
collected (T=0).  GCF will be collected from teeth surrounding the implant site at three sites 
(distal, facial and lingual/palatal), but not the implant site itself to avoid contamination with blood 
post-surgery.  To more closely resemble published guidelines for the control of dental 
postsurgical pain,1 the blinded administration of naproxen sodium 440 (n=15) or acetaminophen 
1000 mg (n=15) will take place immediately after the completion of the surgical procedure, 
before the onset of postoperative pain in most cases. Because of potential screen failures due 
to positive uring drug screens, positive urine pregnancy tests and recent intake of confounding 
medications, we may to consent and enroll up to 35 subjects.  Blinding will be performed by the 
University of Pennsylvania Investigational Drug Services employing an over-encapsulation 
technique.    Study analgesic (naproxen sodium 440 mg or acetaminophen 1000 mg) will be 
ingested by patients with at least 8 ounces of water.  Patients will be queried every 20 minutes 
throughout the 6-hour observation period after study medication ingestion for their pain intensity 
on a validated 10-point numeric scale.28  Additional blood, urine and GCF samples will be 


collected at 1, 2, 4, and 6 hours post study drug administration.  Blood, urine and GCF collection 
will always occur after pain intensity assessments.  If postoperative pain reaches at least a level 
of 4 on the numerical pain scale before 6 hours patients will be allowed to take the supplemental 
medication tramadol 50 mg.  
 
Following the 6-hour sample collection time point, research patients will receive their 
second dose of study medication. Those in the naproxen sodium group will receive 2 placebo 
capsules and those in the acetaminophen group will receive two 500 mg acetaminophen 
capsules under blinded conditions. Patients will then receive post-operative instructions and 
discharged home.  
 
At 12 hours post-surgery (while the patient is at home) patients in the naproxen sodium 
group will receive one active naproxen sodium 220 mg capsule and one placebo capsule and 
those in the acetaminophen group will receive two 500 mg acetaminophen capsules.  Rescue 
tramadol 50 mg will be available (a maximum of one every 6 hours) for both groups if pain 
becomes intolerable.   
 
Upon awakening on Day 2 patients in the naproxen sodium group will ingest one active 
naproxen sodium 220 mg capsule and one placebo capsule, while those in the acetaminophen 
group will consume two 500 mg acetaminophen capsules. At 6 hours those in the naproxen 
sodium group will receive two placebo capsules, followed by one active naproxen sodium 220 
mg capsule and one placebo capsule at 8 hours, two placebo capsules at 12 hours and one 
naproxen sodium capsule at 16 hours.  Those in the acetaminophen group will receive two 
acetaminophen 500 mg capsules at 6 hours, 2 placebo capsules at 8 hours two acetaminophen 
capsules at 12 hours and 2 placebo capsules at 16 hours. The same doing strategy will occur 
on Day 3 as Day 2. A global assessment of both study medications (poor, fair, good, very good 
or excellent will occur at the follow-up visit on Day 3. Rescue tramadol 50 mg will be available 
for insufficient pain relief but no more than one every 6 hours.   The following table illustrates the 
dosing schedules:   


 
Naproxen Sodium Group 
Acetaminophen Group 
Day One: 
Immediately post-surgery 
6 hours post-surgery 
12 hours post-surgery 
 
220 mg x 2 
Placebo x 2 
220 mg x 1 plus placebo x 1 
 
500 mg x 2 
500 mg x 2 
500 mg x 2 
Day Two 
On Awakening 
6 hours post dose one 
8 hours post dose one 
12 hours post dose one 
16 hours post dose one 
 
220 mg x 1 plus placebo x 1 
Placebo x 2 
220 mg x 1 plus placebo x 1 
Placebo x 2 
220 mg x 1 plus placebo x 1 
 
500 mg x 2 
500 mg x 2 
Placebo x 2 
500 mg x 2 
Placebo x 2 
Day Three 
On Awakening 
6 hours post dose one 
8 hours post dose one 
12 hours post dose one 
16 hours post dose one 
 
220 mg x 1 plus placebo x 1 
Placebo x 2 
220 mg x 1 plus placebo x 1 
Placebo x 2 
220 mg x 1 plus placebo x 1 
 
500 mg x 2 
500 mg x 2 
Placebo x 2 
500 mg x 2 
Placebo x 2 
 
Research patients will return to the study site at 24 and 72 hours for single urine, blood and 
GCF collections, pill counts, and verification of pain diary entries.   
 
 
Schedule of Activities 
 
Pre Op 
(T=baseline) 
Surgery 
 Post Op 
(T=0) 
1h 
2h 
4h 
6h 
8h 
12h 
24h 
48h 
72h 
Urine pregnancy 
test, drug and 
cotinine screens 
X 
 
 
 
 
 
 
 
 
 
 


Blood for COX-1 
and COX-2 
activity and 
plasma cytokines 
X 
X2 
X 
X 
X 
X 
 
 
X 
 
X 
Urine for 
measurement of 
PG metabolites  
X 
X2 
X 
X 
X 
X 
 
 
X 
 
X 
GCF for PGE2 
and cytokine 
levels  
X 
X2 
X 
X 
X 
X 
 
 
X 
 
X 
Pain Intensity3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Global 
Assessment of 
Study Medication 
 
 
 
 
 
 
 
 
 
 
 
X 
1 First dose immediately after post op sample.  Dosing continued of fixed schedule for 48 hours, 
prn thereafter 
2 Biological samples will be collected immediately prior to dosing 
3 Pain intensity will also be measured every 20 minutes during the 6 hours inpatient observation 
period at the time immediately prior to the intake of any tramadol and at the time of study 
medication dosing during the inpatient and outpatient period. 
 
Assays 
 
COX-1 and COX-2 inhibition will be determined using ex vivo and in vivo indices of 
enzymatic activity. The ex vivo COX-1 activity assay is based on the capacity of platelets to 
form thromboxane (Tx) A2.26 PGE2 formation in heparinized blood stimulated with 
lipopolysaccharide (LPS) correlates with the activity of induced COX-2 in monocytes.25 
Prostanoids will be quantified by liquid chromatography/mass spectrometry (LC/MS/MS) as 
previously described.25,26  Systemic production of PGE2, PGI2, PGD2, and TxA2 will be 
determined by quantifying urinary concentrations of: 7-hydroxy-5,11-diketotetranorprostane-
1,16-dioic acid (PGEM), 2,3-dinor 6-keto-PGF1α (PGIM), 11,15-dioxo-9α-hydroxy-2,3,4,5-
tetranorprostan-1,20-dioic acid (tetranor PGDM), and 2,3-dinor TxB2 (TxM), respectively. These 


will be measured by LC/MS/MS as previously described.29,30  Results will be normalized by 
comparison to urinary creatinine. 
 
 
Paper strips containing GCF will be pooled at each individual patient time point and  
placed into a labeled Eppendorf microcentrifuge tube in ice and stored at -20°C until assayed. 
Samples will be eluted from the paper strips by the addition of 215 μl of sterile phosphate 
buffered saline (PBS) containing 0.1% bovine serum albumin to each tube and then incubated 
overnight at 4ºC.  PGE2 concentrations will be quantified by LC/MS/MS.   Cytokine levels (IL-6, 
TNF-α, etc) in plasma and GCF will be quantified by ELISA or a commercially available 
multiplex bead assay kit (human cytokine group I kit, BioplexTM Cytokine Assay, Bio-Rad 
Laboratories Inc) following manufacturer instructions.19 
Sample Size and Data Analysis 
 
We plan to enroll up to 35 patients in this pilot study in order to obtain 30 who have 
dosed with study drug.  This sample size is based on our recently published study in patients 
undergoing third molar extraction (N=29), in which we demonstrated that ibuprofen 400 mg 
significantly reduced pain intensity and COX activity compared to placebo.28   
 
The primary efficacy endpoint for the anti-inflammatory effects of naproxen sodium will 
be a comparison of cytokine levels in plasma and GCF between the naproxen sodium and 
acetaminophen groups.  Secondary measures will include ex vivo COX activity in the blood and 
measures of prostaglandin metabolites in the urine. The primary efficacy measure for analgesic 
effects will be comparison between the two treatment groups for the 24 -hour area under the 
pain intensity curve.   Individual pain intensity scores averaged at each time point will also be 
compared between groups.  As an exploratory measure, the time to rescue medication after the 
first dose of naproxen sodium (naproxen sodium 440 mg) and the first two doses 
acetaminophen 1000 mg q 6hr) will also be analyzed, which will be censored at 12 hours. The 
percentage of patients requiring any rescue medication and the total amount rescue medication 
consumed (tramadol mg) will also be calculated and compared between groups.  


For each of the overall blood assay levels, a Repeated Measures ANOVA will be used to 
compare the entire mean profile of naproxen sodium to acetaminophen.  And, for each 
individual time period comparison, an ANOVA will be used to compare the two treatments and 
displayed using time-action curves with means and SEMs.  Pain intensity scores will also be 
analyzed with ANOVA at each time period and Repeated Measures for the entire time 
dependent mean profile comparison. 
 
The efficacy variable ‘time to rescue medication’ will be analyzed with survival analysis, 
a log-rank test, and Kaplan-Meier survival curves. All tests will be two-sided and p< 0.05 will be 
considered statistically significant.  
 
Anticipated Results 
 
We anticipate that patients receiving naproxen sodium 660 mg/day will display a 
significantly higher 24-hour SPID score compared to patients receiving acetaminophen 3000 
mg/day.  In addition, we expect both systemic (urine) and local (GCF) levels of prostaglandins to 
be reduced by naproxen sodium compared to acetaminophen, consistent with its mechanism of 
action as a greater peripheral COX inhibitor.  Moreover, we postulate that naproxen sodium’s 
anti-inflammatory effect, will result in decreased levels of cytokines both locally (GCF) and 
systemically (plasma).  Equally as important, we expect naproxen sodium to be well tolerated in 
this patient population.  Around the clock naproxen sodium 220 mg tablets dosed for the first 48 
hours should provide adequate pain relief with less than 25% of subjects requiring supplemental 
tramadol 50 mg, although the current study is probably not adequately powered to demonstrate 
statistical superiority in this parameter compared to dosed acetaminophen 500 mg X 2 tablets  
Organization and Leadership 
 
This project will be performed by an interdisciplinary team with complementary areas of 
expertise. Drs Hersh and Theken will lead the project. Dr. Hersh will oversee the dental 
surgery component and regulatory aspects of the study. Surgery will be performed by four of his 


colleagues in the PENN School of Dental Medicine, Drs Jonathan Korostoff, Joseph 
Fiorellini, Yu-Cheng Chang and Thomas Yoo. The study will be coordinated by Ms. Stacey 
Secreto-Dankanich, CCRC, EMT, who has coordinated more than 30 analgesic and local 
anesthetic clinical trials with Dr. Hersh and most recently has coordinated two ibuprofen 
inflammatory biomarker 3rd molar postsurgical pain studies. Postsurgical observation of patients 
and sample collection will initially occur in the Periodontal Clinic within the PENN School of 
Dental Medicine on the first floor of the Schattner Building.  For later sampling and pain 
evaluations the patients will be moved to the Clinical Trial Unit on the third floor of the Schattner 
building.   Dr. Theken will be responsible for the processing and analysis of NSAID biomarkers 
and also building and monitoring a REDCap database. Matt Hutcheson MS who was the 
biostatician on 8 FDA clinical trials where Dr Hersh was PI including 2 studies on CTY-5339A 
topical anesthetic spray, 2 studies on Kovanaze®, and 4 studies with Articaine®.  will be 
responsible for clinical trial biostatistics.  Dr Mitchell is a neurobiologist whose laboratory we 
will use (and have used in the past) to process urine, blood and GCF samples. 
Future Efforts 
 
This study should establish the assay sensitivity of a dental implant surgery pain model 
to evaluate analgesics in the OTC dosing range.  In the future, this model can be used to study 
other biomarkers which may impact on individual patient variability to the analgesic effects of 
naproxen sodium including oral and GI microbiome, presurgical measures of anxiety and 
postsurgical pain expectations, naproxen pharmacokinetics and presurgical genomic measures. 
 
 


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