Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents

Objectives: The present study was undertaken to characterize whether the pharmacologic interaction between duloxetine, a balanced serotonergic and noradrenergic reuptake inhibitor, and the non-steroidal anti-inflammatory drug ibuprofen was simply additive, less than additive, or greater than additive (i.e., synergistic) in preclinical models of visceral and inflammatory pain, specifically acetic acid-induced writhing in mice and carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Methods: In the writhing test, male CF-1 mice were injected intraperitoneally with 0.55% acetic acid and 5 min later the number of writhes was counted over a 5-min period. In the carrageenan models, male Sprague-Dawley rats were injected with a 1.5% carrageenan solution into the ventral surface of the hind paw; hypersensitivity to thermal and mechanical stimuli was subsequently evaluated 2 h post-carrageenan. Results: Vehicle or a dose of duloxetine alone (1-100 mg/kg), ibuprofen alone (10-300 mg/kg), or duloxetine and ibuprofen in combination in a dose-ratio of 1:10 duloxetine:ibuprofen were orally administered 30 or 60 min before testing. Isobolographic analysis of the effects of duloxetine in combination with ibuprofen revealed a significant synergistic (greater than additive) interaction between duloxetine and ibuprofen both for reducing acetic acid-induced writhing and carrageenan-induced thermal hyperalgesia, but were additive for reversing mechanical allodynia. Conclusions: Our data indicate that duloxetine and ibuprofen have synergistic efficacy in a visceral and an inflammatory pain model in rodents, and suggest that duloxetine and ibuprofen in combination may provide a useful approach to the clinical treatment of persistent pain, particularly inflammation-related pain. (C) 2006 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.