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Pharmacol Res Perspect. 2016 Feb 27;4(2):e00205. doi: 10.1002/prp2.205. eCollection 2016 Apr.

Mechanisms of the gabapentinoids and α 2 δ-1 calcium channel subunit in neuropathic pain.

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1
Department of Neuroscience, Physiology and Pharmacology University College London Gower Street London WC1E 6BT UK.

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.

KEYWORDS:

Alpha 2 delta 1; calcium channel subunit; gabapentin; neuropathic pain; pregabalin

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