Towards Predicting the Analgesic Response to Ibuprofen Following Third-molar Extraction

NCT03893175 | Completed Phase 1 FDA Drug

• 1 other identifier: 832417
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

This research study will evaluate inter-individual variability in the analgesic response to the non-steroidal anti-inflammatory drug (NSAID) ibuprofen after third molar extraction surgery. It will also investigate demographic, clinical, genetic, and environmental factors that cause this variability.

Conditions

Impacted Third Molar Tooth; Pain, Acute

Keywords

Non-steroidal anti-inflammatory drugs

Outcome Measures

Primary Outcomes (1)

• Analgesic response

  Use of opioid rescue medication

  Up to 7 days after third molar extraction

Secondary Outcomes (15)

• Ibuprofen plasma concentrations

  Up to 7 days

• Acetaminophen plasma concentrations

  Up to 7 days

• Gene expression profiling

  Up to 7 days

• COX-1 activity

  Up to 7 days

• COX-2 activity

  Up to 7 days

Study Arms (2)

Ibuprofen

EXPERIMENTAL

During the double-blind stage, subjects will receive blinded ibuprofen (400 mg by mouth) when pain is at least 4/10 following third molar extraction. During the open-label stage, all subjects will receive ibuprofen (400 mg by mouth) and acetaminophen (500 mg by mouth) to be taken every 4 hours around the clock for the first 2 days after third molar extraction and then as needed for pain up to 7 days after third molar extraction. Rescue medication (oxycodone 5 mg by mouth) will be available if additional analgesic is requested.

Drug: Ibuprofen; Drug: Acetaminophen; Drug: Oxycodone

Placebo

PLACEBO COMPARATOR

During the double-blind stage, subjects will receive blinded placebo when pain is at least 4/10 following third molar extraction. During the open-label stage, all subjects will receive ibuprofen (400 mg by mouth) and acetaminophen (500 mg by mouth) to be taken every 4 hours around the clock for the first 2 days after third molar extraction and then as needed for pain up to 7 days after third molar extraction. Rescue medication (oxycodone 5 mg by mouth) will be available if additional analgesic is requested.

Drug: Ibuprofen; Drug: Acetaminophen; Drug: Placebo; Drug: Oxycodone

Interventions

Ibuprofen DRUG

400 mg by mouth every 4 hours for 2 days after third molar extraction and then as needed for pain up to 7 days after third molar extraction

Also known as: Advil

Ibuprofen; Placebo

Acetaminophen DRUG

500 mg by mouth every 4 hours for 2 days after third molar extraction and then as needed for pain up to 7 days after third molar extraction

Also known as: Tylenol

Ibuprofen; Placebo

Placebo DRUG

By mouth

Placebo

Oxycodone DRUG

5 mg by mouth every 6 hours as needed for pain

Ibuprofen; Placebo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women greater than 18 years of age requiring extraction of at least one impacted mandibular third molar tooth (at least 50% covered with bone).
• Body mass index (BMI) between 18 and 30 kg/m2.
• Absence of other major medical problems or contraindications to surgery or study drugs.
• Has not used tobacco products, including smoking cessation nicotine-containing products (e.g., nicotine patch, nicotine gum), for at least the 3 months prior to screening.
• Female subjects of child bearing potential must be using a medically acceptable method of contraception (oral contraception, Depo-Provera injection, IUD, condom with spermicide, diaphragm, cervical cap, progestin implant, abstinence, tubal ligation, oophorectomy, TAH) throughout the entire study period. All female subjects must consent to a urine pregnancy test at screening and a urine pregnancy test on the day of surgery, which must be negative at all time points.
• Has not ingested caffeine-containing products within 12 hours of surgery.
• All subjects must consent to a urine drug test at screening. Results must be negative. A positive result will be reported to the subject.
• Does not consume more than 1 alcoholic beverage per day on average.
• Subjects must reach a level of at least moderate pain within four hours of surgery completion, with a pain score greater than or equal to 4 on a 0-10 numerical pain scale
• Subjects must be willing and able to complete safety and efficacy diaries.
• An escort must be available to pick up the subject at the end of at the end of the surgical/dosing visit (Visit #2)
• In the opinion of the investigators or research coordinators, subjects must be willing and able to understand and comply with study procedures, including completing safety and efficacy diaries at home.
• Able and willing to provide written informed consent prior to any study procedures being performed.

You may not qualify if:

• Female subjects who are pregnant or nursing a child.
• Subjects who have received an investigational drug or used an experimental medical device within 30 days prior to screening, or who gave a blood donation of ≥ one pint within 8 weeks prior to screening.
• Subjects who are sensitive or allergic to ibuprofen, acetaminophen, or their components.
• Subjects who are sensitive or allergic to aspirin or other NSAIDs.
• Subjects who are sensitive or allergic to oxycodone or other opioids (excluding nausea and constipation).
• Presence of a serious medical condition (e.g. poorly controlled hypertension or diabetes, gastrointestinal disorders such as bleeding ulcer, coagulation or bleeding disorders, significantly impaired cardiac, renal, hepatic, respiratory, or thyroid function) that according to the investigator may interfere with interpretation of the study results or compromise the safety of a potential subject.
• Acute local infection at the time of surgery that could confound post-surgical evaluation.
• Subjects who have taken NSAIDs, including acetaminophen, or other medications for pain, including aspirin or aspirin-containing products within 1 week of study drug administration.
• Subjects who routinely consume high doses of antioxidant vitamins daily (vitamin C \> 1000mg, Vitamin E \> 400IU, Beta Carotene \> 1000IU, Vitamin A \> 5000IU, Selenium \> 200mcg, Folic Acid \> 1mg) during the 2 weeks prior to the start of the study.
• Subjects with any abnormal laboratory value or physical finding that according to the investigator may interfere with interpretation of the study results, be indicative of an underlying disease state, or compromise the safety of a potential subject.
• Subjects who have a history of abuse of narcotics, street drugs, prescription sleeping pills, based upon history and judgment of the Investigator.
• Subjects who are unwilling to provide a blood sample for genetic analyses.
• Employees of the principal investigator, sub-investigators, or relative of an employee who is directly involved in this study.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (10)

• Friedman JW. The prophylactic extraction of third molars: a public health hazard. Am J Public Health. 2007 Sep;97(9):1554-9. doi: 10.2105/AJPH.2006.100271. Epub 2007 Jul 31.

  PMID: 17666691 BACKGROUND

• Gauger EM, Gauger EJ, Desai MJ, Lee DH. Opioid Use After Upper Extremity Surgery. J Hand Surg Am. 2018 May;43(5):470-479. doi: 10.1016/j.jhsa.2018.02.026. Epub 2018 Mar 27.

  PMID: 29602656 BACKGROUND

• Maughan BC, Hersh EV, Shofer FS, Wanner KJ, Archer E, Carrasco LR, Rhodes KV. Unused opioid analgesics and drug disposal following outpatient dental surgery: A randomized controlled trial. Drug Alcohol Depend. 2016 Nov 1;168:328-334. doi: 10.1016/j.drugalcdep.2016.08.016. Epub 2016 Sep 20.

  PMID: 27663358 BACKGROUND

• Thiels CA, Anderson SS, Ubl DS, Hanson KT, Bergquist WJ, Gray RJ, Gazelka HM, Cima RR, Habermann EB. Wide Variation and Overprescription of Opioids After Elective Surgery. Ann Surg. 2017 Oct;266(4):564-573. doi: 10.1097/SLA.0000000000002365.

  PMID: 28697049 BACKGROUND

• Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Available from http://www.ncbi.nlm.nih.gov/books/NBK424857/

  PMID: 28252892 BACKGROUND

• Compton WM, Jones CM, Baldwin GT. Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. N Engl J Med. 2016 Jan 14;374(2):154-63. doi: 10.1056/NEJMra1508490. No abstract available.

  PMID: 26760086 BACKGROUND

• Cooper SA, Engel J, Ladov M, Precheur H, Rosenheck A, Rauch D. Analgesic efficacy of an ibuprofen-codeine combination. Pharmacotherapy. 1982 May-Jun;2(3):162-7. doi: 10.1002/j.1875-9114.1982.tb04528.x.

  PMID: 6763202 BACKGROUND

• Hersh EV, Levin LM, Adamson D, Christensen S, Kiersch TA, Noveck R, Watson G 2nd, Lyon JA. Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain. Clin Ther. 2004 Aug;26(8):1215-27. doi: 10.1016/s0149-2918(04)80033-x.

  PMID: 15476903 BACKGROUND

• Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, Hong D, Secreto SA. Ibuprofen liquigel for oral surgery pain. Clin Ther. 2000 Nov;22(11):1306-18. doi: 10.1016/s0149-2918(00)83027-1.

  PMID: 11117655 BACKGROUND

• Desjardins PJ, Black PM, Daniels S, Bird SR, Fitzgerald BJ, Petruschke RA, Tershakovec A, Chang DJ. A randomized controlled study comparing rofecoxib, diclofenac sodium, and placebo in post-bunionectomy pain. Curr Med Res Opin. 2004 Oct;20(10):1523-37. doi: 10.1185/030079904X3069.

  PMID: 15462686 BACKGROUND

MeSH Terms

Conditions

Acute Pain

Interventions

Ibuprofen; Acetaminophen; Oxycodone

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Codeine; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Tilo Grosser, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Katherine N Theken, PharmD, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Elliot V Hersh, DMD, MS, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• John Farrar, MD, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Administration of ibuprofen vs. placebo will be masked.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Subjects will be randomized to receive either ibuprofen or placebo after third molar extraction when pain intensity is at least 4/10. Four hours after the masked ibuprofen or placebo, all subjects will receive open-label ibuprofen + acetaminophen to be taken every 4 hours for the first 2 days and then as needed for up to 7 days after oral surgery. Oxycodone will be available as a rescue medication if additional analgesic is requested.

Study Record Dates

• First Submitted: March 22, 2019
• First Posted: March 28, 2019
• Study Start: May 10, 2019
• Primary Completion: March 2, 2022
• Study Completion: March 2, 2022
• Last Updated: July 24, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)