New targets for neuropathic pain therapeutics

Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional 'small-molecule' approach.