Clinical trial NCT06539741: Variability in Analgesic Response to Ibuprofen
Official title: Mechanisms of Variability in the Analgesic Response to Ibuprofen Following Third Molar Extraction
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Impacted Third Molar Tooth
Pain, Acute
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute of Dental and Craniofacial Research (NIDCR)
First posted: 2024-08-06
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients presenting for surgical extraction of partial or full bony impacted mandibular third molars at the Oral Surgery Clinics at Penn Dental Medicine

Brief summary: Nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, are recommended as first-line treatment for post-surgical dental pain. However, there is variability in analgesic response, and some patients require supplemental opioids for adequate pain relief. The goal of this study is to identify the factors that contribute to the need for opioid after third molar extraction to help limit unnecessary opioid prescriptions in patients who will have good pain relief with ibuprofen alone.

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.

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 as 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.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Ability to take oral medication and be willing to adhere to the study treatment regimen
4. 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).
5. Absence of other major medical problems or contraindications to surgery or study drugs.
6. 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.
7. Has not ingested caffeine-containing products within 12 hours of surgery.
8. All subjects must consent to a urine drug test at screening. Results must be negative (except for THC) unless the subject is on a stable dose of a non-analgesic drug for a legitimate medical purpose. A positive test for THC will be permitted and the frequency of use will be documented. A positive result will be reported to the subject.
9. Does not consume more than 1 alcoholic beverage per day on average.
10. 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
11. Subjects must be willing and able to complete safety and efficacy diaries.
12. An escort must be available to pick up the subject at the end of at the end of the surgical/dosing visit (Visit #2).

Exclusion Criteria:

1. Female subjects who are pregnant or nursing a child.
2. 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.
3. Subjects who are sensitive or allergic to ibuprofen, acetaminophen, or their components.
4. Subjects who are sensitive or allergic to aspirin or other NSAIDs.
5. Subjects who are sensitive or allergic to oxycodone or other opioids (excluding nausea and constipation).
6. 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.
7. Acute local infection at the time of surgery that could confound post-surgical evaluation.
8. 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). 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.
9. 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.
10. Subjects who have a history of opioid use disorder or other substance use disorder, based upon history and judgment of the Investigator.
11. Subjects who are unwilling to provide a blood sample for genetic analyses.
12. Employees of the principal investigator, sub-investigators, or relative of an employee who is directly involved in this study.

Primary outcomes:
measure: Supplemental Opioid Use
timeFrame: Up to 7 days after third molar extraction
Secondary outcomes:
measure: Gene Expression Profiling
timeFrame: Up to 7 days after third molar extraction
measure: COX-1 activity
timeFrame: Up to 7 days after third molar extraction
measure: COX-2 activity
timeFrame: Up to 7 days after third molar extraction
measure: DNA sequencing
timeFrame: 1 day
measure: Pain intensity score
timeFrame: Up to 7 days after third molar extraction
measure: Inflammatory mediator profiling
timeFrame: Up to 7 days after third molar extraction
measure: Complete blood count with differential
timeFrame: Up to 7 days after third molar extraction
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania School of Dental Medicine
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Katherine N Theken, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: