GSE120596
Variability in the Analgesic Response to Ibuprofen Following Third Molar Extraction is Associated with Differences in Activation of the Cyclooxygenase Pathway
It has long been recognized that there is substantial inter-individual variability in the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), but the mechanisms underlying this variability are not well understood.  In order to characterize the factors associated with heterogeneity in response to ibuprofen, we performed functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, biochemical assays, and gene expression analysis in twenty-nine healthy subjects who underwent third molar extraction. Subjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design.  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 prostaglandin metabolites (p<0.05). Ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication) and complete responders (N=10, no rescue medication). This variability in analgesic efficacy was not associated with demographic/clinical characteristics, markers of systemic inflammation, or ibuprofen pharmacokinetics. Complete responders exhibited less suppression of urinary prostaglandin metabolites and greater induction of serum tumor necrosis factor-a and interleukin 8, compared to partial responders (p<0.05).  Partial responders exhibited more alterations in gene expression in peripheral blood mononuclear cells after surgery, with an enrichment in inflammatory pathways.  These findings suggest that activation of the prostanoid biosynthetic pathway and regulation of the inflammatory response to surgery differs between partial and complete responders.  Future studies are necessary to elucidate the molecular mechanisms underlying this variability and identify biomarkers that are predictive of ibuprofen response. Overall design: Human subjects were given Ibuprofen (400 mg; n=19) or placebo (n=10) following surgical extraction of their third molars. Subjects given Ibuprofen were retrospectively classified as partial responders (n=9) if they required rescue medication (hydrocodone 5 mg/acetaminophen 325 mg), or full responders (n=10) if they did not. All subjects in the placebo group received rescue medication.  Blood was collected from subjects before surgery (baseline) and at two time points following surgery (post-surgery 1, post-surgery 2). Both post-surgery samples were collected after subjects were given drug/placebo. Peripheral blood mononuclear cell (PBMCs) were isolated from blood samples and their RNA content was assayed via RNA-seq. The following samples were dropped from normalization and final analyses due to low read depths: GSM3405457 (1004_post-surgery_1), GSM3405459 (1005_post-surgery_1), GSM3405462 (1007_baseline), GSM3405463 (1007_post-surgery_1), GSM3405464 (1008_baseline), GSM3405465 (1008_post-surgery_1), GSM3405466 (1008_post-surgery_2), GSM3405468 (1011_post-surgery_1), GSM3405469 (1011_post-surgery_2), GSM3405472 (1012_post-surgery_2), GSM3405491 (1020_baseline).