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

NCT ID: NCT03893175

Last Updated: 2025-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-10
• Study Completion Date: 2022-03-02

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.

Detailed Description

The dramatic increase in opioid prescriptions over the past years has been linked to the concomitant rise in opioid addiction and to deaths from opioid abuse. Young adults' initial exposure to opioid analgesics is often following extraction of their impacted third molars, with an average of 5,000,000 cases in the USA per year. Over-prescribing of opioids for surgical pain, often 2-5 times more than patients actually use, further exacerbates this problem, as patients tend to save leftover pills rather than discard them. Up to 70% of individuals who become addicted to prescription opioids had access to leftover pills prescribed for others. This is particularly troubling as the odds of transitioning to heroin from prescription opioid abuse are much higher than other suspected gateway drugs, about 40 fold greater than non-gateway drug users. Heroin is now often laced with fentanyl derivatives making overdose and death more likely in even the most opioid tolerant individuals.

Multiple studies have demonstrated that non-addicting nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac are effective in relieving pain after dental impaction surgery, being at least equally efficacious to optimal doses of immediate release opioid formulations combined with acetaminophen. However, these assessments of pain relief represent average scores and approximately 22% and 50% of individuals required additional opioid-containing rescue analgesics when ibuprofen and diclofenac were employed at FDA-approved dosages. A deeper understanding of the sources of variability in pain relief should allow improvements in the overall efficacy of NSAIDs by targeting treatment to those who are most likely to receive sufficient pain relief. Thus, optimizing pain therapy with NSAIDs by personalization would be expected to help limit the unnecessary prescription of highly addicting immediate release opioids. Moreover, these results may have applicability to other types of pain that are driven by inflammation.

Conditions

Impacted Third Molar Tooth; Pain, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

Ibuprofen

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.

Group Type: EXPERIMENTAL

Ibuprofen

Intervention Type: 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

Acetaminophen

Intervention Type: 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

Oxycodone

Intervention Type: DRUG

5 mg by mouth every 6 hours as needed for pain

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Ibuprofen

Intervention Type: 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

Acetaminophen

Intervention Type: 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

Placebo

Intervention Type: DRUG

By mouth

Oxycodone

Intervention Type: DRUG

5 mg by mouth every 6 hours as needed for pain

Interventions

Ibuprofen

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

Intervention Type: DRUG

Acetaminophen

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

Intervention Type: DRUG

Placebo

By mouth

Intervention Type: DRUG

Oxycodone

5 mg by mouth every 6 hours as needed for pain

Intervention Type: DRUG

Other Intervention Names

Advil; Tylenol

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.
• Use of any confounding prescription or non-prescription drug within 24 hours of the surgical procedure, including analgesics, sedating antihistamine, sedative, alcohol, or CNS/psychotropic agents (i.e. sleep aids, benzodiazepines, performance/attention enhancers, marijuana, anti-depressants). Hormonal contraceptives, hormone replacement therapy (including males taking testosterone as a hormone replacement to treat a documented low testosterone level), or thyroid replacement hormones are allowed. Individuals taking other/additional chronic stable medications can be considered on a case-by-case basis for inclusion in the study if agreed upon by judgment of the investigator.
• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tilo Grosser, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Katherine N Theken, PharmD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Elliot V Hersh, DMD, MS, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

John Farrar, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

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

Philadelphia, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 17666691 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29602656 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27663358 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28697049 (View on PubMed)

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/

Reference Type: BACKGROUND

PMID: 28252892 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26760086 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 6763202 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15476903 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11117655 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15462686 (View on PubMed)

Other Identifiers

832417

Identifier Type: -

Identifier Source: org_study_id