Gabapentin Marches Toward Mechanism

Researchers are approaching a new level of understanding for the neuropathic pain-relief mechanisms of gabapentin. And the momentum generated by such a discovery may bring better tidings for the drug's difficult, if promising, history.

First approved by the US Food and Drug Administration (FDA) in 1993 as an add-on epilepsy treatment, the drug, marketed as Neurontin, led its manufacturer, Pfizer, into trouble. Pfizer, successor to the original maker, Warner-Lambert, agreed last year to pay $430 million to settle charges that Warner-Lambert had promoted the drug for various unapproved indications including restless leg syndrome, trigeminal neuralgia, and migraine. But meanwhile, gabapentin had become a blockbuster, as doctors had begun widely prescribing it for those same uses. Studies have since shown that use may be justified for at least one condition: shingles-associated neuropathic pain.¹ The FDA approved gabapentin for this in 2002.

But in a new setback, Pfizer lost a bid to keep competitors from launching generic versions of gabapentin late last year. Pfizer responded to these troubles by launching its own generic version and developing the analog, pregabalin. Pregabalin, which Pfizer claims is more potent, is approved in Europe for the treatment of neuropathic pain. The FDA has indicated it will approve it if certain issues are resolved, according to Pfizer. But as with most pain medications, use has preceded an understanding of the mechanisms involved. "It wasn't rational drug design," notes Frank Porreca, professor of pharmacology at the University of Arizona.

A longstanding theory claimed gabapentin worked by binding the Ca²⁺ channel a₂d-1 subunit. It was hard to prove this because a₂d-1 knockout mice tend to die or be so dysfunctional as to be of little use for research. But at the Society for Neuroscience annual meeting in San Diego last October, Pfizer researchers reported they had resolved this by modifying just one amino acid in a a₂d-1 subunit to produce mice who were unresponsive to pregabalin but otherwise normal.² This shows pregabalin works by modulating calcium flow at the channel, which in turn affects the flow of neurotransmitters, says Pfizer research fellow Charles Taylor. The researchers tested gabapentin in a more limited scope and found similar results, Taylor says, although the findings have yet to be published. Their mechanisms of action "are pretty much identical or similar," he adds, although each may have slightly different affinity for a different variety of the subunit.

The study is "clever, clever, clever," says Tony Yaksh, an anesthesiology professor at University of California, San Diego, and could inspire searches for drugs that bind the same subunits, or other subunits of the same channels. Combined with previous work, he adds, the study shows that these drugs act primarily in the spinal cord, where a₂d-1 subunits are upregulated in neuropathic pain states. This contributes to growing evidence, he says, that the spinal cord is more than what researchers have long assumed it is--a simple transmitter of messages, like a telephone relay station. "It's more like a computer."