New molecules for the treatment of pain

To inform on preclinical and early clinical advances in the effort to identify novel classes of analgesic drugs.

Human genetic and animal preclinical studies have identified several mechanisms that appear to make important contributions to abnormal pain states. From human genetics, a small number of patients with mutations in the genes encoding nerve growth factor/TrkA signaling and in a particular sodium channel subunit (SCN9a, encoding Nav1.7) show congenital analgesia with limited other effects. There are, therefore, considerable hopes that pharmacological manipulation of these systems in chronic pain patients might be an effective analgesic strategy. A substantial body of preclinical work has focussed on interactions between the immune and the nervous system and this has led to the identification of a number of novel putative inflammatory mediators and receptors, which are being explored as potential analgesic targets. A recent preclinical effort has studied intracellular signaling cascades recruited in the transition from acute to chronic pain states - the analgesic opportunities on offer here are being pursued in early clinical trials.

Existing analgesic drugs are small in number, limited in efficacy and associated with significant side-effects. There is, therefore, a need for new pain medications. In the last decade or so, clinical and preclinical research have progressed rapidly and this work has identified multiple plausible drug targets, which are currently being evaluated. We review here the rationale of some of the most promising mechanisms and report on progress in drug development.