Variability in the Analgesic Response to Ibuprofen Following Third-Molar Extraction

Objectives: Understanding sources of variability in response to nonsteroidal anti-inflammatory drugs (NSAIDs) may facilitate personalized treatment of inflammatory pain. We evaluated the relationship between ibuprofen pharmacokinetics, markers of drug response, pain relief, and regional cerebral blood flow (CBF) by functional magnetic resonance imaging (fMRI) following third-molar extraction.
Methods: Twenty-nine healthy subjects (18-34 years, 13 women) underwent removal of ≥2 partial or full-bony impacted third-molars. While local anesthesia dissipated, CBF was measured by arterial spin labeling MRI, and pain was assessed by a numeric scale (0-10). When pain reached ≥4/10, rapid-acting ibuprofen (400 mg;N=19) or placebo (N=10) was administered in a randomized, double-blind design. fMRI and pain assessment were repeated for ~1.5hr or until subjects requested rescue medication (acetaminophen/hydrocodone). Ibuprofen pharmacokinetics, gene expression, serum inflammatory mediators, ex vivo cyclooxygenase (COX)-1 and 2 activity, and urinary prostaglandin (PG) metabolites were evaluated.
Results: Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in CBF in brain regions associated with pain processing, and inhibition of ex vivo COX-1 and COX-2 activity and urinary PG metabolites(p<0.05). Post-surgery, COX-2 mRNA expression in peripheral blood mononuclear cells and serum interleukin-6 concentrations were increased(p<0.05), consistent with induction of systemic inflammation. Ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication) and complete responders (N=10, no rescue medication). Variability in analgesic efficacy was not associated with demographic/clinical characteristics, markers of systemic inflammation, or ibuprofen pharmacokinetics. However, partial responders had greater reduction in urinary PG metabolites following ibuprofen(p<0.05), compared to complete responders.
Conclusions: Ibuprofen relieved third-molar extraction pain, but analgesic efficacy was variable among individuals. The need for opioid rescue medication was associated with molecular indices of COX inhibition. Identifying mechanisms that contribute to variability in pain relief may enable personalization of NSAIDs and reduce use of opioid analgesics.