Next Generation Anticonvulsants GABA Enhancers

Vigabatrin (SabrilĀ®) - newly approved (2009) antiepileptic drug indicated for refractory complex partial seizures in adults. Vigabatrin inhibits the breakdown of GABA by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. Shown to cause irreversible bilateral concentric visual field constriction in 30% of patients -baseline vision testing and eye exams q3mo. Not likely to find common use in pain medicine due to high incidence of vision loss.

Tiagabine (GabitrilĀ®): An antiepilepsy drug available in 2, 4, 12, 16 mg tablets. Binds to recognition sites associated with the GABA uptake carrier. It is thought that tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of postsynaptic cells. Approved in 1997, FDA required revised package insert in 2005 secondary to reports showing an association with new onset seizures and status epilepticus in patients without epilepsy. In most cases, patients were using concomitant medications that lower the seizure threshold. Off-label use of Gabitril [bipolar, neuropathy, depression, posttraumatic stress disorders (PTSD)] is now strongly discouraged by the FDA.

Ganaxolone (INN, also known as CCD-1042): a neurosteroid related to pregnanolone which has sedative, anxiolytic, and anticonvulsant effects. It is a potent and selective positive allosteric modulator of GABA-A receptors.

Phase 2b studies of ganaxolone are ongoing to study and evaluate safety, tolerability, and efficacy in adults with complex partial seizures. Any effect on neuropathic pain has yet to be formally studied.

Retigabine: Acts on potassium ion channels and effects GABA neurotransmission by action at the GABA-A receptor. Retigabine is a psychoactive drug and research chemical under development as a novel anticonvulsant agent. Its acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action completely different from those of presently marketed antiepileptics. Retigabine is currently in phase III clinical trials as an adjunctive treatment for partial-onset seizures in adult patients with refractory epilepsy. GlaxoSmithKline (GSK) and Valeant Pharmaceuticals International (VRX) announced on October 30, 2009 that they filed a New Drug Application with the US Food and Drug Administration (FDA) for retigabine, used as adjunctive therapy to treat adult epilepsy patients with partial-onset seizures. Preliminary animal models have shown effectiveness in diminishing neuropathic pain (Blackburn-Munro and Jensen 2003).

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