Demonstration of OTC Naproxen Sodium's (Aleve's) Anti-inflammatory Action in Dental Implant Surgery Patients
Phase: PHASE4
Conditions: Osseointegrated Dental Implantation, Pain, Acute
Sponsor: Hersh, Elliot V., DMD, MS, PhD

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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