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

Pain, Acute Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04694300
• Other study ID #: 844440
• Secondary ID: IIR
• Status: Completed
• Phase: Phase 4
• Start date: February 7, 2021
• Est. completion date: August 28, 2022

Study information

• Verified date: May 2024
• Source: Hersh, Elliot V., DMD, MS, PhD
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 28, 2022
• Est. primary completion date: August 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Pain
• Osseointegrated Dental Implantation
• Pain, Acute

Intervention

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.
• 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.
• Tramadol
50 mg by mouth every 6 hours as needed for pain

Locations

Country	Name	City	State
United States	University of Pennsylvania School of Dental Medicine	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Hersh, Elliot V., DMD, MS, PhD	University of Pennsylvania

Country where clinical trial is conducted

United States, 

References & Publications (18)

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Aghaloo T, Pi-Anfruns J, Moshaverinia A, Sim D, Grogan T, Hadaya D. The Effects of Systemic Diseases and Medications on Implant Osseointegration: A Systematic Review. Int J Oral Maxillofac Implants. 2019 Suppl;34:s35-s49. doi: 10.11607/jomi.19suppl.g3. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Pietruski JK, Pietruska MD, Stokowska W, Pattarelli GM. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in patients treated with dental implants. Rocz Akad Med Bialymst. 2001;46:28-37. — View Citation

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. — View Citation

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. — View Citation

Theken KN, Chen M, Wall DL, Pham T, Secreto SA, Yoo TH, Rascon AN, Chang YC, Korostoff JM, Mitchell CH, Hersh EV. A randomized, double-blind pilot study of analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen following dental impla — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Up to 6 hours
Primary	Pain Intensity Scores From 6 Through 72 Hours (Multi-dose Phase)	Pain intensity scores where 0 = no pain and 10 = worst possible pain	6-72 hours Post initial Dose
Primary	Peak Plasma IL-6 Concentrations	Plasma IL-6 concentrations 6 hours after treatment measured by ELISA	6 hours
Primary	Plasma IL-6 Change From Baseline	Percent change in plasma IL-6 levels at 6 hours after treatment relative to baseline	6 hours post dose
Secondary	Rescue Analgesic Use	Number of patients requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) in each treatment group	0-6 hours
Secondary	Rescue Medication Use Outpatient Phase (6-72 Hours)	Number of patients requiring opioid rescue medication during outpatient phase in both treatment groups	6-72 hours
Secondary	Peak GCF IL-1ß Levels	Levels of IL-1ß in gingival crevicular fluid measured at 24 hours after treatment	24 hours post-dose
Secondary	COX-1 Activity Percent of Baseline (Pre-surgery)	Cyclooxygenase (COX)-1 activity was evaluated ex vivo by quantifying serum thromboxane B2 levels	6 hours post dose
Secondary	COX-2 Activity	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
Secondary	Peak GCF IL-8levels	Levels of IL-8 in gingival crevicular fluid measured at 24 hours after treatment	24 hours post-dose

External Links

•   17 Dental Implant Industry Statistics and Trends.