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

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.

Study Overview

• Status: Completed
• Conditions: Pain, Acute; Impacted Third Molar Tooth
• Intervention / Treatment: Drug: Placebo; Drug: Ibuprofen; Drug: Acetaminophen; Drug: Oxycodone

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: 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; Other Names: Advil; 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; Other Names: Tylenol; Drug: Oxycodone; 5 mg by mouth every 6 hours as needed for pain
PLACEBO_COMPARATOR: 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.	Drug: Placebo; By mouth; Drug: 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; Other Names: Advil; 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; Other Names: Tylenol; Drug: Oxycodone; 5 mg by mouth every 6 hours as needed for pain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analgesic response	Need for opioid rescue medication after administration of blinded study drug	Up to 4 hours after taking blinded ibuprofen or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composition of the gut microbiome	Assessed by evaluating the microbes present in a stool sample	1 day
DNA sequencing	Assessment of genetic variation	1 day
Ibuprofen plasma concentrations	Assessed by measuring the amount of ibuprofen in plasma	Up to 7 days
Acetaminophen plasma concentrations	Assessed by measuring the amount of acetaminophen in plasma	Up to 7 days
Gene expression profiling	mRNA levels will be measured in peripheral blood mononuclear cells	Up to 7 days
COX-1 activity	COX-1 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.	Up to 7 days
COX-2 activity	COX-2 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.	Up to 7 days
Urinary metabolomics	Assessed by measuring levels of metabolites in urine	Up to 7 days
Plasma metabolomics	Assessed by measuring levels of metabolites in plasma	Up to 7 days
Composition of the oral microbiome	Assessed by evaluating the microbes present in an oral swab	1 day
Pain intensity score	Rating of pain from 0 (no pain) to 10 (worst imaginable pain)	Up to 7 days
Inflammatory mediator profiling	Assessment of cytokines in plasma	Up to 7 days
C-reactive protein	Assessment C-reactive protein in serum	Up to 7 days
Procalcitonin levels	Assessment of procalcitonin in serum	Up to 7 days
Complete blood count with differential	Assessment of proportions of red blood cells, white blood cells, and platelets in whole blood	Up to 7 days

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Katherine N Theken, PharmD, PhD, University of Pennsylvania; Principal Investigator: John Farrar, MD, PhD, University of Pennsylvania

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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/
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 10, 2019
• Primary Completion (ACTUAL): March 2, 2022
• Study Completion (ACTUAL): March 2, 2022

Study Registration Dates

• First Submitted: March 22, 2019
• First Submitted That Met QC Criteria: March 25, 2019
• First Posted (ACTUAL): March 28, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 19, 2022
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Non-steroidal anti-inflammatory drugs
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Ibuprofen; Oxycodone
• Other Study ID Numbers: 832417

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No