Editors' Note: What Is the Mechanism of Therapeutic and Adverse Effects of Gabapentinoids?

Dr. Benarroch reviewed the mechanisms underlying the therapeutic and adverse effects of gabapentinoids such as gabapentin and pregabalin. The author noted that the efficacy of these drugs for neuropathic pain, restless legs syndrome, and focal seizures is primarily attributed to their inhibition of the α2 subunit of presynaptic voltage-gated calcium channels, which decreases neurotransmitter release. He discussed the relevance of this inhibitory action in the potential induction of cerebellar ataxia by gabapentinoids. In response, Dr. Gazulla et al. argue that GABAergic effects of these medications are also important, noting that gabapentin has been shown to increase the expression of GABAA receptors, inhibitory tone in the cerebellum, and brain GABA concentration in patients, whereas pregabalin has been shown to increase neuronal calcium influx, which facilitates neurotransmission. They argue that gabapentinoids could actually help treat ataxia in diseases involving GABA deficiency. Responding to these comments, Dr. Benarroch notes that he did cite work finding increased expression of GABAA receptors with gabapentin use but did not cite a pilot study of pregabalin for ataxia because the review was focused on mechanisms relating to the current clinical use of gabapentinoids. He agrees that increased GABAergic transmission by these drugs may benefit disorders affecting Purkinje cells and other inhibitory neurons such as periodic alternating nystagmus but cautions that the mechanisms of ataxia are complex and that further studies are needed to confirm potential beneficial effects of gabapentinoids in cerebellar ataxia. This exchange highlights uncertainties regarding the potential therapeutic vs adverse effects of gabapentinoids in ataxia and other cerebellar disorders.

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