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

Sponsor

Hersh, Elliot V., DMD, MS, PhD (Other)

Overall Status

Recruiting

CT.gov ID

NCT04694300

Collaborator

University of Pennsylvania (Other)

Enrollment

Location

Arms

13.9

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Double blind, randomized, active-controlled, two armsDouble 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 :

Feb 7, 2021

Anticipated Primary Completion Date :

Feb 6, 2022

Anticipated Study Completion Date :

Apr 6, 2022

Arms and Interventions

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

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: 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

Drug: Tramadol

50 mg by mouth every 6 hours as needed for pain

Other Names:

Ultram

Outcome Measures

Primary Outcome Measures

Prostaglandin E2 concentrations employing liquid chromatography/mass spectrometry [Up to 3 days]
Assessment of PGE2 in urine and gingival crevicular fluid
Tumor necrosis factor concentrations employing ELISA [Up to 3 days]
Assessment of TNF levels in plasma
Interleukin 6 concentrations employing ELISA [Up to 3 days]
Assessment of IL-6 levels in plasma

Secondary Outcome Measures

Pain intensity scores on numeric pain intensity scale [Up to 6 hours]
Pain intensity scores where 0 = no pain and 10 = worst possible pain
Rescue analgesic use [Up to 3 days]
Need for opioid rescue medication (tramadol) in addition to blinded study medication
24-hour area under the pain intensity curve (SPI24) [1 day]
Derived from 0-10 numeric pain intensity scale (0= no pain, 10=worst possible pain)
COX-2 activity [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.
COX-1 activity [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania School of Dental Medicine	Philadelphia	Pennsylvania	United States	19104-6030

Sponsors and Collaborators

Hersh, Elliot V., DMD, MS, PhD
University of Pennsylvania

Investigators

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