Synergistic symptom-specific effects of ketorolac–tramadol and ketorolac–pregabalin in a rat model of peripheral neuropathy

Abstract

Although current neuropathic pain treatment guidelines do not recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), whether NSAIDs can serve as a useful adjuvant to conventional multimodal therapy remains unclear. The spared nerve injury (SNI) rats rapidly developed profound and long-lasting spontaneous and evoked pain behaviors, including mechanical and cold allodynia of the ipsilateral hind paw. At day 5, we first characterized the nociceptive responses to ketorolac, tramadol, pregabalin, and their combinations. We found that tramadol and pregabalin exerted dose-dependent analgesic effects on both spontaneous and evoked behaviors. However, ketorolac alone did not suppress any behaviors regardless of the dose. Ketorolac-tramadol and ketorolac-pregabalin produced variable degrees of additive suppression of spontaneous and evoked behavioral responses. Cold allodynia was profoundly diminished after ketorolac was added to ineffective pregabalin or tramadol. Mechanical allodynia was markedly attenuated by ketorolac-pregabalin but less so by ketorolac-tramadol mixtures. Our data demonstrated that an NSAID alone failed to relieve spontaneous or evoked pain behaviors in the rat SNI model, but when combined with a weak opioid and α-2-δ-ligand produced a profound synergistic analgesic effect on cold allodynia and discrepant efficacy for mechanical allodynia and spontaneous pain.