Mechanisms of the gabapentinoids and α₂δ‐1 calcium channel subunit in neuropathic pain

Abstract

The gabapentinoid drugs gabapentin and pregabalin are key front‐line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ‐1 and α 2 δ‐2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α 2 δ‐1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α 2 δ‐1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.

Etiology and Pharmacology of Neuropathic Pain

“…This very much complicates the search for effective therapeutic targets. Although gabapentinoids may only bind to one specific target, the a2d-1 subunit of voltage-gated Ca 2+ channels (Gee et al, 1996;Field et al, 2006;Offord and Isom, 2015), this interaction has multiple consequences for synaptic transmission, neuron-selective actions, and network excitability at the spinal level (Biggs et al, 2014;Alles and Smith, 2016;Alles et al, 2017) and within higher brain centers (Suzuki et al, 2005;Eroglu et al, 2009;Suto et al, 2014;Crosby et al, 2015;Patel and Dickenson, 2016a;Bannister et al, 2017b); this multiplicity of effect may explain their therapeutic effectiveness. The appreciation of this concept has led to the evidence-based development of drugs that will affect multiple targets Zamponi et al, 2015).…”

Preclinic and clinic effectiveness of gabapentin and pregabalin for treatment of neuropathic pain in rats and diabetic patients

“…There are conflicting reports regarding the efficacy of gabapentinoids in inflammatory and neuropathic animal models against mechanical and thermal hypersensitivity [12]. While indirect comparisons show similar efficacy and tolerability profile [13], there are few comparative studies of pregabalin and gabapentin for neuropathic pain including PHN, PDN and spinal cord injury-related neuropathic pain.…”

Untitled

“…It binds to the α2δ (alpha-2-delta) subunit of the voltage-dependent calcium channel in the central nervous system providing an anti-hyperalgesic and anti-allodynic effect specific for its action at the CaVα2δ-1 subunit 4 . But there is no evidence of its role in preventing progression of nerve damage in STZ induced neurotoxicity.…”