Increased analgesic efficacy in combinations of gabapentin with non-steroidal anti-inflammatory drugs inhibiting cyclooxygenase 2

Background and objectives: Good analgesic efficacy has been reported in combinations of gabapentin with certain non-steroidal anti-inflammatory drugs (NSAIDs); although existing data are limited and ambiguous. In this study, gabapentin was combined with several NSAIDs, cyclooxygenase (COX) inhibitors, to assess analgesic efficacy of the combinations relative to differences in COX-1 and COX-2 inhibition. Methods: Antinociceptive activity was studied using isobolographic analysis following acetic acid induced abdominal constrictions in mice (writhing test). Synergy (supra-additivity) was measured by the interaction index γ (the ratio between experimental and theoretical ED 50; the lower the γ value, the stronger the synergy). Results: All tested drugs produced dose-dependent antinociceptive effects. The isobolographic analysis carried out using equipotent dose ratios showed that synergy (supra-additivity) was strongest in the combination of gabapentin with etoricoxib, the most selective COX-2 inhibitor (γ: 0.13). Combinations of gabapentin with celecoxib, diclofenac, and nimesulide, which are less selective COX-2 inhibitors, was weaker, but still significantly supra-additive, (γ: 0.30, 0.35, 0.58, respectively); in combination with ibuprofen, a nonselective COX inhibitor, the effect was additive (γ: 1.12). In combination of gabapentin with FR 122047, a selective COX-1 inhibitor, the effect was sub-additive (γ: 1.45). The degree of synergy (γ) correlated with the relative efficacy of COX-2 inhibition (IC50 COX-1/COX- 2). Conclusions: Our results suggest that analgesic efficacy of combinations of gabapentin with NSAIDs was directly related to their relative efficacy in inhibiting COX-2. Our results also suggest further investigation into the therapeutic potential of combinations of gabapentinoids with selective or preferential COX-2 inhibitors for pain control.