OTC Naproxen and Acetaminophen Anti-Inflammatory Action in Dental Implant Patients

May 7, 2024 updated by: Hersh, Elliot V., DMD, MS, PhD

Demonstration of OTC Naproxen Sodium's (Aleve's) Anti-inflammatory Action in Dental Implant Surgery Patients

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-6030
        • University of Pennsylvania School of Dental Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subject requires surgical placement of one or two (adjacent) dental implants
  • Ability to read and sign informed consent
  • Males and females for 18-75 years of age
  • Non-smokers
  • Negative urine drug screen

Exclusion Criteria

  • 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), a history of GI ulcers, liver or kidney disease, and anticoagulant or lithium intake.
  • History of an allergic reaction to any pain reliever/fever reducer
  • 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 participant denies smoking history
  • History of systemic steroid use over 2 weeks within last 2 years.
  • Poor oral hygiene on a non-compliant individual.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Naproxen sodium
Naproxen sodium 440 mg followed by naproxen sodium 220 mg q 8h (max 660 mg/day)
Drug: Naproxen

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.

Other Names:
  • Aleve
Drug: Tramadol
50 mg by mouth every 6 hours as needed for pain
Other Names:
  • Ultram
Active Comparator: Acetaminophen
Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert)
Drug: Tramadol
50 mg by mouth every 6 hours as needed for pain
Other Names:
  • Ultram
Drug: Acetaminophen
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.
Other Names:
  • Extra Strength Tylenol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pain Intensity Scores on Numeric Pain Intensity Scale 0-6 Hours
Time Frame: Up to 6 hours
Median maximum pain intensity scores where 0 = no pain and 10 = worst possible pain
Up to 6 hours
Pain Intensity Scores From 6 Through 72 Hours (Multi-dose Phase)
Time Frame: 6-72 hours Post initial Dose
Pain intensity scores where 0 = no pain and 10 = worst possible pain
6-72 hours Post initial Dose
Peak Plasma IL-6 Concentrations
Time Frame: 6 hours
Plasma IL-6 concentrations 6 hours after treatment measured by ELISA
6 hours
Plasma IL-6 Change From Baseline
Time Frame: 6 hours post dose
Percent change in plasma IL-6 levels at 6 hours after treatment relative to baseline
6 hours post dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rescue Analgesic Use
Time Frame: 0-6 hours
Number of patients requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) in each treatment group
0-6 hours
Rescue Medication Use Outpatient Phase (6-72 Hours)
Time Frame: 6-72 hours
Number of patients requiring opioid rescue medication during outpatient phase in both treatment groups
6-72 hours
Peak GCF IL-1β Levels
Time Frame: 24 hours post-dose
Levels of IL-1β in gingival crevicular fluid measured at 24 hours after treatment
24 hours post-dose
COX-1 Activity Percent of Baseline (Pre-surgery)
Time Frame: 6 hours post dose
Cyclooxygenase (COX)-1 activity was evaluated ex vivo by quantifying serum thromboxane B2 levels
6 hours post dose
COX-2 Activity
Time Frame: 6 hours post-dose
COX-2 activity was evaluated ex vivo by quantifying plasma prostaglandin (PG)E2 levels following lipopolysaccharide (LPS) stimulation in whole blood,
6 hours post-dose
Peak GCF IL-8levels
Time Frame: 24 hours post-dose
Levels of IL-8 in gingival crevicular fluid measured at 24 hours after treatment
24 hours post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hersh, Elliot V., DMD, MS, PhD

Collaborators

University of Pennsylvania

Investigators

  • Principal Investigator: Katherine N Theken, PharmD, PhD, University of Pennsylvania School of Dental Medicine and Medicine
  • Principal Investigator: Elliot V Hersh, DMD, MS, PhD, University of Pennsylvania

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 7, 2021

Primary Completion (Actual)

August 28, 2022

Study Completion (Actual)

August 28, 2022

Study Registration Dates

First Submitted

December 31, 2020

First Submitted That Met QC Criteria

January 1, 2021

First Posted (Actual)

January 5, 2021

Study Record Updates

Last Update Posted (Actual)

May 16, 2024

Last Update Submitted That Met QC Criteria

May 7, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 844440
  • IIR (Other Grant/Funding Number: Bayer Pharmaceutical)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

IPD will not be shared. This is a pilot, exploratory study.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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