Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents.
OBJECTIVE
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 2h 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.
Jones
Carrie K
CK
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Peters
Steven C
SC
Shannon
Harlan E
HE
D019342:Acetic Acid; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D004357:Drug Synergism; D000068736:Duloxetine Hydrochloride; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007052:Ibuprofen / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009638:Norepinephrine / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D019342:Acetic Acid; D018759:Adrenergic Uptake Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D000068736:Duloxetine Hydrochloride; D007052:Ibuprofen; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes