Breaking barriers to novel analgesic drug development

Pain is the primary reason why people seek medical care; more than 40% of the US population is affected by chronic pain.Opioids, which are the most commonly used and often the most effective class of analgesics, produce tolerance, dependence and constipation, and are associated with major abuse liabilities. The respiratory depression associated with high doses has led to a catastrophic increase in the number of drug overdose deaths in the United States.Several new or previously overlooked targets are gaining significant attention. In the field of G-protein-coupled receptors (GPCRs), these include new ligands targeting opioid receptor heteromers, different opioid receptor subtypes and biased agonists. Non-opioid GPCRs currently being pursued include cannabinoid receptor 2 (CB2), angiotensin type 2 receptor (AT2R) and chemokine receptors.Various academic and industry groups are pursuing ion channel strategies by targeting sodium, potassium and calcium channels — specifically, certain Nav1.7, Nav1.8 and voltage-dependent calcium channel (Cavs) ligands are showing particular promise in early preclinical and clinical trials.Several enzyme targets that modulate pain pathways are also being pursued.Despite considerable efforts, there have been several high-profile failures of novel analgesics in the clinic.Barriers that need to be overcome to develop efficacious analgesics include issues related to the lack of predictability of preclinical models in certain contexts, the translation of pathways from animal models to humans, exaggerated placebo effects and issues with clinical trial design.