Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain

Abstract

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.

Figure 1

Study design. fMRI, functional magnetic resonance imaging.

Figure 2

Interindividual variability in analgesic response to ibuprofen. (a) Kaplan–Meier plots depicting time to rescue medication administration by response group (placebo: n = 10; partial responders: n = 9; complete responders: n = 10; P < 0.001 for all comparisons in the log‐rank test). (b) Pain scores at each pain assessment prior to rescue medication administration by response group. Error bars indicate interquartile range (*P < 0.05; Kruskal–Wallis test). Vertical dashed line indicates time of study drug administration. (c) Change of pain scores relative to predrug (0 minutes) scores up to 30 minutes (*P < 0.05; Kruskal–Wallis test). (d) Heatmap depicting change from predrug of the integrated cerebral blood flow measurements in pain regions (NeuroSynth pain map) by individual patients.

Figure 3

Comparison of urinary prostaglandin (PG) metabolite levels after surgery in partial and complete responders. Urinary metabolites of (a) prostaglandin E (PGE)₂, (b) prostacyclin (PGI)₂, (c) PGD₂, and (d) thromboxane (Tx)A₂ are expressed as percent change from baseline. Crossbars indicate median and interquartile range. *P < 0.05 by Wilcoxon rank‐sum test. PGDM, 11,15‐dioxo‐9α‐hydroxy‐2,3,4,5‐tetranorprostane‐1,20‐dioic acid; PGEM, 7‐hydroxy‐5,11‐diketotetranorprostane‐1,16‐dioic acid; PGIM, 2,3‐dinor 6‐keto‐PGF_1α. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Comparison of serum inflammatory mediators after surgery in partial and complete responders. Serum levels of (a) tumor necrosis factor‐α (TNF‐α), (b) interleukin (IL)‐8, (c) IL‐6, (d) IL‐10, and (e) monocyte chemoattractant protein (MCP)‐1 are expressed as percent change from baseline. Crossbars indicate median and interquartile range. *P < 0.05 by Wilcoxon rank‐sum test. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5

RNA sequencing analysis of peripheral blood mononuclear cells. (a) Venn diagram depicting overlap among the response groups in genes differentially expressed at the second postsurgery time point compared to baseline (q < 0.05). (b) Heatmap depicting differentially expressed genes between partial and complete responders at the second postsurgery time point (q < 0.2).