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

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ClinicalTrials.gov Identifier: NCT04694300
Recruitment Status : Recruiting
First Posted : January 5, 2021
Last Update Posted : February 16, 2021
Sponsor:
Collaborator:
University of Pennsylvania
Information provided by (Responsible Party):
Hersh, Elliot V., DMD, MS, PhD

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.

Condition or disease Intervention/treatment Phase
Osseointegrated Dental Implantation Pain, Acute Drug: Naproxen Drug: Acetaminophen Drug: Tramadol Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double blind, randomized, active-controlled, two arms
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Administration of naproxen or acetaminophen will be masked by over-encapsulation
Primary Purpose: Basic Science
Official Title: Demonstration of OTC Naproxen Sodium's (Aleve's) Anti-inflammatory Action in Dental Implant Surgery Patients
Actual Study Start Date : February 7, 2021
Estimated Primary Completion Date : February 6, 2022
Estimated Study Completion Date : April 6, 2022

Resource links provided by the National Library of Medicine


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 Name: Aleve

Drug: Tramadol
50 mg by mouth every 6 hours as needed for pain
Other Name: Ultram

Active Comparator: Acetaminophen
Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert)
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 Name: Extra Strength Tylenol

Drug: Tramadol
50 mg by mouth every 6 hours as needed for pain
Other Name: Ultram




Primary Outcome Measures :
  1. Prostaglandin E2 concentrations employing liquid chromatography/mass spectrometry [ Time Frame: Up to 3 days ]
    Assessment of PGE2 in urine and gingival crevicular fluid

  2. Tumor necrosis factor concentrations employing ELISA [ Time Frame: Up to 3 days ]
    Assessment of TNF levels in plasma

  3. Interleukin 6 concentrations employing ELISA [ Time Frame: Up to 3 days ]
    Assessment of IL-6 levels in plasma


Secondary Outcome Measures :
  1. Pain intensity scores on numeric pain intensity scale [ Time Frame: Up to 6 hours ]
    Pain intensity scores where 0 = no pain and 10 = worst possible pain

  2. Rescue analgesic use [ Time Frame: Up to 3 days ]
    Need for opioid rescue medication (tramadol) in addition to blinded study medication

  3. 24-hour area under the pain intensity curve (SPI24) [ Time Frame: 1 day ]
    Derived from 0-10 numeric pain intensity scale (0= no pain, 10=worst possible pain)

  4. COX-2 activity [ Time Frame: Up to 3 days ]
    COX-2 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine and gingival crevicular fluid.

  5. COX-1 activity [ Time Frame: Up to 3 days ]
    COX-1 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04694300


Contacts
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Contact: Elliot V Hersh, DMD, MS, PhD 215-898-9686 evhersh@upenn.edu
Contact: Katherine N Theken, PharmD, PhD 215-573-9592 ktheken@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
University of Pennsylvania School of Dental Medicine Recruiting
Philadelphia, Pennsylvania, United States, 19104-6030
Contact: Elliot V Hersh, DMD, MS, PhD    215-898-9686    evhersh@upenn.edu   
Contact: Stacey Secreto, EMT, CCRC    215-746-8871    secreto@upenn.edu   
Principal Investigator: Elliot V Hersh, DMD, MS, PhD         
Sub-Investigator: Jonathan Korostoff, DMD, PhD         
Sub-Investigator: Yu Cheng Chang, DMD         
Sub-Investigator: Joseph Fiorellini, DMD, DScD         
Sub-Investigator: Thomas Yoo, DMD         
Principal Investigator: Katherine N Theken, PharmD, PhD         
Sub-Investigator: Claire Mitchell, PhD         
Sponsors and Collaborators
Hersh, Elliot V., DMD, MS, PhD
University of Pennsylvania
Investigators
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Principal Investigator: Elliot V Hersh, DMD, MS, PhD University of Pennsylvania
Principal Investigator: Katherine N Theken, PharmD, PhD University of Pennsylvania School of Dental Medicine and Medicine
Additional Information:
Publications:

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Responsible Party: Hersh, Elliot V., DMD, MS, PhD
ClinicalTrials.gov Identifier: NCT04694300    
Other Study ID Numbers: 844440
IIR ( Other Grant/Funding Number: Bayer Pharmaceutical )
First Posted: January 5, 2021    Key Record Dates
Last Update Posted: February 16, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: IPD will not be shared. This is a pilot, exploratory study.

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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
Keywords provided by Hersh, Elliot V., DMD, MS, PhD:
Naproxen sodium
Acetaminophen
Postsurgical dental pain
Prostaglandins
Tumor Necrosis Factor
Interleukins
Additional relevant MeSH terms:
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Acute Pain
Pain
Neurologic Manifestations
Acetaminophen
Naproxen
Tramadol
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action