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

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.

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.