Since the initial demonstration of an essential role for SCN9A, the gene that encodes sodium channel Nav1.7, in human pain (1) , attention has focused on the role of the channel in nociception. The channel is expressed in peripheral sensory neurons, and the initial hope was that selective Nav1.7 blockers that were peripherally restricted might produce analgesia at the same level as that observed in the loss of function mutants. However, this hope has not been fulfilled and potent analgesics have proved elusive. Mechanistic studies have demonstrated that Nav1.7 has pleiotropic roles in pain pathways. The first evidence for this came from microarray analysis of Nav1.7 null mutant sensory neurons. Deletion of SCN9A in sensory neurons results in a complex range of transcriptional changes, including a dramatic increase in the expression of preproenkephalin mRNA. A major role for endogenous opioids in Nav1.7 null analgesia has been demonstrated in both mice and two human null mutants, as naloxone reverses much of the analgesia (2). However, enhanced opioid peptide levels alone do not account for this analgesic mechanism (3). Interestingly, opioid receptors themselves also seem to be potentiated, possibly as a result of altered intracellular sodium levels (4). Apart from a link to the opioid system Nav1.7 has a remarkable role as an integrator of small depolarisations that may contribute to its essential role in nociceptive signalling (5) . In addition, neuropeptide release from sensory neurons has been shown to be abolished in the absence of Nav1.7 (2). More recently, a remarkable transfer of Nav1.7 from sensor neurons to dorsal horn neurons has been observed. Sensory neuron-derived Nav1.7 seems to play a significant role in contributing to dorsal horn neuron excitability (6 ) .Thus we have a remarkable range of actions of Nav1.7, many within the dorsal horn of the spinal cord, that are important for normal pain pathways. What are the consequences of these mechanistic observations for an analgesic drug development? It is now clear that highly selective Nav1.7 antagonists are not analgesic. However, when combined with low dose opioids or enkephalinase inhibitors, useful analgesia can be achieved (7). This has potential utility in dealing with the disastrous opioid analgesia crisis in the United States. However, the contribution of potentiated opioid receptors, and the role of dorsal horn Nav1.7 channels may limit the synergistic approach of Nav1.7 inhibitors and opioid peptides. If so, gene therapy, silencing or deleting the SCN9A gene may be a necessary approach to exploit the full potential of Nav1.7 as an analgesic drug target,