Na(v)1.7 and other voltage-gated sodium channels as drug targets for pain relief

Introduction: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects. Areas covered: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Na(v)1.7, 1.8 and 1.9 can cause pain, whilst loss of function Na(v)1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Na(v)1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Na(v)1.7 expression. Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Na(v)1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Na(v)1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Na(v)1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant.