The discovery and development of analgesics: new mechanisms, new modalities

Abstract

Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met.

Figure 1. Analgesic launches from 1990 to 2010.

The majority of new drug launches were reformulations of existing pharmaceuticals. NRI, norepinephrine reuptake inhibitor; SAIDs, steroidal antiinflammatory drugs; SNRI, serotonin-norepinephrine reuptake inhibitor.

Figure 2. Schematic diagram showing the relative binding sites of ziconotide and pregabalin to voltage-gated calcium channel complex.

Ziconotide binds to the pore-forming α₁ subunit, whereas pregabalin binds to the accessory subunit α₂δ. Figure adapted with permission from Sigma-Aldrich.