Mirogabalin: could it be the next generation gabapentin or pregabalin?

Abstract

Except for carbamazepine for trigeminal neuralgia, gabapentinoid anticonvulsants have been the standard for the treatment of neuropathic pain. Pregabalin, which followed gabapentin, was developed with the benefit of rapid peak blood concentration and better bioavailability. Mirogabalin besylate (DS-5565, Tarlige^®) shows greater sustained analgesia due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion (DRG). Additionally, it produces a lower level of central nervous system-specific adverse drug reactions (ADRs), due to a low affinity to, and rapid dissociation from, the α2δ-2 subunits in the cerebellum. Maximum plasma concentration is achieved in less than 1 hour, compared to 1 hour for pregabalin and 3 hours for gabapentin. The plasma protein binding is relatively low, at less than 25%. As with all gabapentinoids, it is also largely excreted via the kidneys in an unchanged form, and so the administration dose should also be adjusted according to renal function. The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin and over 1,200 mg of gabapentin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel, safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain in the DRG and lower ADRs in the cerebellum.

Keywords: Analgesia; Anticonvulsants; Ataxia; Calcium Channels; Cerebellum; Dizziness; Gabapentin; Ganglia; Mirogabalin; Neuralgia; Pregabalin; Sleepiness; Spinal.

Fig. 1

A schematic illustration of the mechanisms of action for mirogabalin. Mirogabalin has a high affinity to and slow dissociation from the α₂δ-1 subunits in the dorsal root ganglia (DRGs), producing greater therapeutic effects; it also has a low affinity to and fast dissociation from the α₂δ-2 subunits in the cerebellum, producing lesser adverse drug reactions. In general, various mechanisms of action for gabapentinoids are suggested from inside the cell, membrane, and synapse. (1) Gabapentinoids inhibit forward (anterograde) trafficking of voltage-gated calcium channels (VGCCs) (from the endoplasmic reticulum through the Golgi complex to the cell membrane) intracellularly. Inhibition of anterograde trafficking reduces VGCCs, calcium entry, and excitatory amino acids (glutamates). (2) They inhibit the Rab-11-dependent final recycling of endosomal VGCCs intracellularly, resulting in reduced excitatory neurotransmitter release in the synapse. The small guanosine triphosphatases (GTPases, Rab) are the main regulators of intracellular membrane trafficking, from formation of transport vesicles to their fusion into the membranes. Reduced recycling of endosomal VGCCs results in reduced transmembrane VGCCs, calcium entry into the cell, and glutamate in the synapse. (3) They inhibit astrocyte-derived thrombospondin (TSP, extracellular matrix protein)-mediated excitatory synapse formation extracellularly (reduction of excitatory synaptogenesis). (4) They stimulate glutamate uptake by excitatory amino acid transporters (EAATs) extracellularly. (5) Gabapentinoids may show inhibition of descending serotonergic facilitation, stimulation of descending inhibition, anti-inflammatory effect, and influence on the affective component of pain. A magnified illustration for the transmembrane VGCC is shown in the upper left (in the DRGs) and right (in the cerebellum) quadrants. Adapted from Chincholkar M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br J Anaesth 2018; 120: 1315-34 [14].