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Osseointegrated Dental ImplantationPhase 4NCT04694300

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

A Phase 4 study testing Naproxen, Acetaminophen and Tramadol in people with Osseointegrated Dental Implantation and Pain, Acute, run by Hersh, Elliot V., DMD, MS, PhD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Naproxen, Acetaminophen and Tramadol
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteUnited States
Study dates
7 Feb 2021to 28 Aug 2022
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • University of Pennsylvania School of Dental Medicine

    Philadelphia, Pennsylvania, 19104-6030

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Naproxen, Acetaminophen, Tramadol
Keywords
Naproxen sodium, Acetaminophen, Postsurgical dental pain, Prostaglandins, Interleukins
Medical subject headings
Acute Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NaproxenDrug

    Also called Aleve

    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.

  • AcetaminophenDrug

    Also called Extra Strength Tylenol

    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.

  • TramadolDrug

    Also called Ultram

    50 mg by mouth every 6 hours as needed for pain

Study groups in NCT04694300
Study groupRoleWhat they receive
Naproxen sodiumExperimentalNaproxen sodium 440 mg followed by naproxen sodium 220 mg q 8h (max 660 mg/day)
Receives: Drug: Naproxen; Drug: Tramadol
AcetaminophenActive comparatorAcetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert)
Receives: Drug: Acetaminophen; Drug: Tramadol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Pain Intensity Scores on Numeric Pain Intensity Scale 0-6 Hours

    Median maximum pain intensity scores where 0 = no pain and 10 = worst possible pain

    Measured: Up to 6 hours

  2. Pain Intensity Scores From 6 Through 72 Hours (Multi-dose Phase)

    Pain intensity scores where 0 = no pain and 10 = worst possible pain

    Measured: 6-72 hours Post initial Dose

  3. Peak Plasma IL-6 Concentrations

    Plasma IL-6 concentrations 6 hours after treatment measured by ELISA

    Measured: 6 hours

  4. Plasma IL-6 Change From Baseline

    Percent change in plasma IL-6 levels at 6 hours after treatment relative to baseline

    Measured: 6 hours post dose

Secondary outcomes (6)
  1. Rescue Analgesic Use

    Number of patients requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) in each treatment group

    Measured: 0-6 hours

  2. Rescue Medication Use Outpatient Phase (6-72 Hours)

    Number of patients requiring opioid rescue medication during outpatient phase in both treatment groups

    Measured: 6-72 hours

  3. Peak GCF IL-1β Levels

    Levels of IL-1β in gingival crevicular fluid measured at 24 hours after treatment

    Measured: 24 hours post-dose

  4. COX-1 Activity Percent of Baseline (Pre-surgery)

    Cyclooxygenase (COX)-1 activity was evaluated ex vivo by quantifying serum thromboxane B2 levels

    Measured: 6 hours post dose

  5. COX-2 Activity

    COX-2 activity was evaluated ex vivo by quantifying plasma prostaglandin (PG)E2 levels following lipopolysaccharide (LPS) stimulation in whole blood,

    Measured: 6 hours post-dose

  6. Peak GCF IL-8levels

    Levels of IL-8 in gingival crevicular fluid measured at 24 hours after treatment

    Measured: 24 hours post-dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jan 2021
  2. Study start7 Feb 2021
  3. Primary completion28 Aug 2022
  4. Study completion28 Aug 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Model description
Double blind, randomized, active-controlled, two arms
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04694300
Sponsor's protocol ID
844440
Other IDs
IIR
Status last verified
May 2024
First submitted
31 Dec 2020
Last updated
16 May 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: IPD will not be shared. This is a pilot, exploratory study.

Publications

  • Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice. J Am Dent Assoc. 2013 Aug;144(8):898-908. doi: 10.14219/jada.archive.2013.0207.

    PubMed 23904576
  • Hersh EV, Moore PA, Grosser T, Polomano RC, Farrar JT, Saraghi M, Juska SA, Mitchell CH, Theken KN. Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain. J Dent Res. 2020 Jul;99(7):777-786. doi: 10.1177/0022034520914254. Epub 2020 Apr 14.

    PubMed 32286125
  • Deeb GR, Deeb JG, Agarwal V, Laskin DM. Use of transalveolar sutures to maintain vestibular depth and manipulate keratinized tissue following alveolar ridge reduction and implant placement for mandibular prosthesis. J Oral Maxillofac Surg. 2015 Jan;73(1):48-52. doi: 10.1016/j.joms.2014.07.022. Epub 2014 Jul 30.

    PubMed 25315314
  • Schmitt A, Zarb GA. The longitudinal clinical effectiveness of osseointegrated dental implants for single-tooth replacement. Int J Prosthodont. 1993 Mar-Apr;6(2):197-202.

    PubMed 8329098
  • Zarb GA, Schmitt A. The longitudinal clinical effectiveness of osseointegrated dental implants in posterior partially edentulous patients. Int J Prosthodont. 1993 Mar-Apr;6(2):189-96.

    PubMed 8329097
  • Elani HW, Starr JR, Da Silva JD, Gallucci GO. Trends in Dental Implant Use in the U.S., 1999-2016, and Projections to 2026. J Dent Res. 2018 Dec;97(13):1424-1430. doi: 10.1177/0022034518792567. Epub 2018 Aug 3.

    PubMed 30075090
  • Bockow R, Korostoff J, Pinto A, Hutcheson M, Secreto SA, Bodner L, Hersh EV. Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac. Compend Contin Educ Dent. 2013 Sep;34(8):570-6.

    PubMed 24564610
  • Alissa R, Sakka S, Oliver R, Horner K, Esposito M, Worthington HV, Coulthard P. Influence of ibuprofen on bone healing around dental implants: a randomised double-blind placebo-controlled clinical study. Eur J Oral Implantol. 2009 Autumn;2(3):185-99.

    PubMed 20467629
  • Hashem AA, Claffey NM, O'Connell B. Pain and anxiety following the placement of dental implants. Int J Oral Maxillofac Implants. 2006 Nov-Dec;21(6):943-50.

    PubMed 17190305
  • Al-Khabbaz AK, Griffin TJ, Al-Shammari KF. Assessment of pain associated with the surgical placement of dental implants. J Periodontol. 2007 Feb;78(2):239-46. doi: 10.1902/jop.2007.060032.

    PubMed 17274712
  • Samieirad S, Afrasiabi H, Tohidi E, Qolizade M, Shaban B, Hashemipour MA, Doaltian Shirvan I. Evaluation of caffeine versus codeine for pain and swelling management after implant surgeries: A triple blind clinical trial. J Craniomaxillofac Surg. 2017 Oct;45(10):1614-1621. doi: 10.1016/j.jcms.2017.06.014. Epub 2017 Jul 5.

    PubMed 28864284
  • Emecen-Huja P, Eubank TD, Shapiro V, Yildiz V, Tatakis DN, Leblebicioglu B. Peri-implant versus periodontal wound healing. J Clin Periodontol. 2013 Aug;40(8):816-24. doi: 10.1111/jcpe.12127. Epub 2013 Jun 18.

    PubMed 23772674
  • Aboyoussef H, Carter C, Jandinski JJ, Panagakos FS. Detection of prostaglandin E2 and matrix metalloproteinases in implant crevicular fluid. Int J Oral Maxillofac Implants. 1998 Sep-Oct;13(5):689-96.

    PubMed 9796154
  • O'Brien TP, Roszkowski MT, Wolff LF, Hinrichs JE, Hargreaves KM. Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery. J Periodontol. 1996 Dec;67(12):1307-16. doi: 10.1902/jop.1996.67.12.1307.

    PubMed 8997678
  • Li S, Yang Y, Yu C, Yao Y, Wu Y, Qian L, Cheung CW. Dexmedetomidine Analgesia Effects in Patients Undergoing Dental Implant Surgery and Its Impact on Postoperative Inflammatory and Oxidative Stress. Oxid Med Cell Longev. 2015;2015:186736. doi: 10.1155/2015/186736. Epub 2015 Jun 15.

    PubMed 26171113

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Naproxen, Acetaminophen and Tramadol in people with Osseointegrated Dental Implantation and Pain, Acute, run by Hersh, Elliot V., DMD, MS, PhD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pain Intensity Scores on Numeric Pain Intensity Scale 0-6 Hours (time frame: Up to 6 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04694300, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2024.

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