Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs often used to treat pain following third molar extraction. Ibuprofen is an NSAID that provides excellent pain relief for most patients when prescribed for this purpose. However, some individuals need a short course of opioids in addition to achieve sufficient relief. The goal of this study was to understand why this inter-individual variability exists so that we may be able to predict with precision which patients will need opioids prescribed.

Ibuprofen works by inhibiting cyclooxygenase (COX) enzymes. COX-2 functions by producing prostaglandins, including PGE2, which cause inflammation and sensitization of nociceptors to pain stimuli. Therefore, I was interested to test whether pharmacokinetics prevented sufficient inhibition of prostaglandin production in patients who needed opioids. I hypothesized that my ex vivo assays would reveal suppression of COX-2 in all Ibuprofen-treated patients.

The study design involved removal of third molars from healthy subjects and evaluation of pharmacologic and pain intensity responses at several timepoints. Patients were randomized to receive either Ibuprofen 400 mg or placebo after the surgery, then all patients were instructed to take Ibuprofen 400 mg and acetaminophen 500 mg every four hours after discharge. COX-2 activity was measured by quantifying PGE2 in plasma samples treated with lipopolysaccharide (LPS), an inflammatory stimulus. 

I found that COX-2 activity was lower in Ibuprofen-treated patients than in placebo-treated patients. Within each treatment group, COX-2 activity was not related to use of opioids for additional pain relief. Because Ibuprofen suppressed COX-2 activity in all treated patients, it is evident that Ibuprofen is effective in inhibiting COX-2, and variability in pain relief does not result from pharmacokinetic effects. Therefore, increasing dosage for patients who do not achieve sufficient relief will not improve efficacy. Future studies may explore upstream or downstream components of the COX-2 pathway, examine the COX-1 pathway, or measure COX activity in vivo to evaluate association with degree of pain relief.