In some ways, neuropathic pain seems an odd choice of focus for a small start-up. It comes in many forms and its mechanisms are poorly understood. Moreover, the size and strength of those with stakes in the pain market might be another reason for emerging companies to steer clear. Fortunately, they're not. The unmet need is huge: Only one in two patients actually get some relief from existing drugs, in part because their mechanisms of action are fairly generalized. There remains plenty to be done in identifying and understanding the precise mechanisms behind the various flavors of neuropathic pain. For those whocan figure out new approaches to pain or new uses in pain for failed or overlooked compounds -- the companies profiled in this issue are doing both -- there's a big reward at the end: Sales of neuropathic pain therapies in the seven major pharmaceutical markets reached nearly $5 billion in 2007.

Australia's Spinifex Pharmaceuticals has identified a compound that it believes represents an entirely new mechanism of action for neuropathic pain. Its lead agent is a G-protein coupled receptor (GPCR) antagonist, in Phase I trials for post-herpetic neuralgia. Although the GPCR class is one of the most popular drug targets across the industry, Spinifex claims that the GPCR it's focused on is not commonly associated with pain research.

Arcion Therapeutics is focusing its development efforts on an existing chemical entity, clonidine, but its theory is more novel: that much or all of the abnormal pain signaling associated with neuropathic pain occurs in the skin. Thus it is trying to develop a topical form of clonidine, an alpha-2 adrenergic receptor agonist already marketed for high blood pressure. Arcion has uncovered a variety of mechanisms by which clonidine may relieve pain and hopes to soon begin a Phase IIb trial in diabetic neuropathy. The goal: a product that is easy to use and avoids many of the side effects associated with current treatments.