The evolving understanding of the analgesic mechanism of action of flupirtine

What is known and Objective: Flupirtine is a widely known analgesic drug that is approved for the treatment of acute and chronic pain, particularly musculoskeletal pain. However, it is neither an NSAID nor an opioid. Given pending trials of flupirtine for the treatment of fibromyalgia pain, an understanding of flupirtine’s (unique?) mechanism of analgesic action is of both clinical and basic science interest. Our objective was to trace the evolution of the understanding of flupirtine’s mechanism of analgesic action to its current status. Methods: Information was gathered from various bibliographic sources, such as PubMed and others, and integrated for insight into postulated mechanism(s) of analgesic action of flupirtine. Results and Discussion: The major site of action of flupirtine appears to be the central nervous system (both spinal and supraspinal). Initial studies suggested involvement of descending adrenergic pathways, followed by a postulated (indirect) action at N‐Methyl‐D‐aspartate (NMDA) receptors, to the present view of activation of a G‐protein regulated inwardly rectifying K⁺ (GIRK) ion channel. The mechanism and relative contribution of metabolites (such as the active acetylated moiety) has not been fully defined. What is new and Conclusion: Flurpirtine might represent a novel class of analgesic agent. As such, it could be useful for the treatment of types of pains normally not amenable to conventional (NSAID or opioid) pharmacotherapy. It could also spawn new avenues of analgesic drug discovery efforts.