Historical Overview on Baclofen, the Only GABAB Receptor Agonist Approved and Available for Clinical Use

Baclofen was synthesized in 1962 as a component of a group of ß-aryl-halogenated GABA derivatives capable of crossing the blood-brain barrier and, thus, exerting inhibitory effects on the central nervous system. At that time, the role of GABA as a neurotransmitter had not been fully discovered, and nothing was known about its receptors. The clinical development of baclofen was based on its muscle-relaxant effects. Ten years after its synthesis, baclofen was registered in Europe as Lioresal®; registration in the United States occurred in 1977. Over the following decade, baclofen became the drug of choice for the treatment of spasticity and muscle spasms. Anecdotal reports from patients taking baclofen for its approved indications led to the identification of additional, possible uses (often supported by accumulating findings on the central and peripheral functions of GABA neurotransmission). Among these new indications, it is worth mentioning the treatment of substance use disorder, which actually represents the sole, recent advancement in terms of authorizations. Since the early 1980s, baclofen actions at specific GABA receptors (named GABAB) were discovered. It is now hoped that future research will focus on (i) possible new clinical applications of baclofen and (ii) new GABAB receptor agonists, including those naturally occurring, that would hopefully come alongside baclofen and possibly extend its therapeutic prospects.