Gabapentin was designed to mimic the neurotransmitter GABA.
In epilepsy, it’s thought that gabapentin stops seizures by reducing the abnormal electrical activity in the brain.
With nerve pain and migraine, it’s thought to interfere with pain messages travelling through the brain and down the spine to block pain.
It does not, however, bind to GABA receptors. Its mechanism of action as an antiepileptic agent likely involves its inhibition of the alpha 2-delta subunit of voltage-gated calcium channels .
It was first approved as an anticonvulsant in 1994 in the US and is now available worldwide. It was also approved in the US for postherpetic neuralgia in 2002 and is used commonly to treat neuropathic pain. Gabapentin is renally excreted and is not an enzyme-inducing anticonvulsant.
Gabapentin use resulted in increased fracture in the Canadian population-based study . There is limited study on effects of gabapentin on BMD. Several studies have evaluated adults taking anticonvulsant that included gabapentin. These data suggest that gabapentin may cause bone loss.
The previously described MrOS study found significant bone loss at the hip in older men prescribed gabapentin . There are no reports evaluating whether gabapentin treatment results in changes in markers of bone and mineral metabolism.
Future studies should focus on whether gabapentin, which is commonly used for multiple indications, adversely affects bone.
Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear.
The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the alpha2delta-1 subunit.
This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.
The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures.
Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels.
However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase.
Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters.
Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity.
Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.