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

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ClinicalTrials.gov Identifier: NCT03893175
Recruitment Status : Recruiting
First Posted : March 28, 2019
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Impacted Third Molar Tooth Pain, Acute Drug: Ibuprofen Drug: Acetaminophen Drug: Placebo Drug: Oxycodone Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Administration of ibuprofen vs. placebo will be masked.
Primary Purpose: Other
Official Title: Towards Predicting the Analgesic Response to Ibuprofen Following Third-molar Extraction
Actual Study Start Date : May 10, 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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: 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 Name: 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 Name: Tylenol

Drug: Placebo
By mouth

Drug: Oxycodone
5 mg by mouth every 6 hours as needed for pain




Primary Outcome Measures :
  1. Analgesic response [ Time Frame: Up to 4 hours after taking blinded ibuprofen or placebo ]
    Need for opioid rescue medication after administration of blinded study drug


Secondary Outcome Measures :
  1. Ibuprofen plasma concentrations [ Time Frame: Up to 7 days ]
    Assessed by measuring the amount of ibuprofen in plasma

  2. Acetaminophen plasma concentrations [ Time Frame: Up to 7 days ]
    Assessed by measuring the amount of acetaminophen in plasma

  3. Gene expression profiling [ Time Frame: Up to 7 days ]
    mRNA levels will be measured in peripheral blood mononuclear cells

  4. COX-1 activity [ Time Frame: Up to 7 days ]
    COX-1 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.

  5. COX-2 activity [ Time Frame: Up to 7 days ]
    COX-2 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.

  6. DNA sequencing [ Time Frame: 1 day ]
    Assessment of genetic variation

  7. Urinary metabolomics [ Time Frame: Up to 7 days ]
    Assessed by measuring levels of metabolites in urine

  8. Plasma metabolomics [ Time Frame: Up to 7 days ]
    Assessed by measuring levels of metabolites in plasma

  9. Composition of the gut microbiome [ Time Frame: 1 day ]
    Assessed by evaluating the microbes present in a stool sample

  10. Composition of the oral microbiome [ Time Frame: 1 day ]
    Assessed by evaluating the microbes present in an oral swab

  11. Pain intensity score [ Time Frame: Up to 7 days ]
    Rating of pain from 0 (no pain) to 10 (worst imaginable pain)

  12. Inflammatory mediator profiling [ Time Frame: Up to 7 days ]
    Assessment of cytokines in plasma

  13. C-reactive protein [ Time Frame: Up to 7 days ]
    Assessment C-reactive protein in serum

  14. Procalcitonin levels [ Time Frame: Up to 7 days ]
    Assessment of procalcitonin in serum

  15. Complete blood count with differential [ Time Frame: Up to 7 days ]
    Assessment of proportions of red blood cells, white blood cells, and platelets in whole blood



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03893175


Contacts
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Contact: Stacey A Secreto 215-746-8871 secreto@upenn.edu

Locations
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United States, Pennsylvania
Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Stacey A Secreto    215-746-8871    secreto@upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: 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

Publications:

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03893175     History of Changes
Other Study ID Numbers: 832417
First Posted: March 28, 2019    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by University of Pennsylvania:
Non-steroidal anti-inflammatory drugs
Additional relevant MeSH terms:
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Ibuprofen
Acute Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Acetaminophen
Oxycodone
Analgesics
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Analgesics, Opioid
Narcotics
Central Nervous System Depressants