Lost but making progress—Where will new analgesic drugs come from?

Abstract

There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies.

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

“…Undersampling and limited reproducibility inherent to commonly used shotgun proteomics approaches (16 -19) represent major obstacles for proteome-based systems biology. This is in stark contrast to the emerging importance of "network medicine" as a powerful strategy to correct functional misalignments of complex cellular processes (2,76,95). Consequently, it might provide promising tools for achieving analgesia as exemplified by studies linking mitochondrial dysfunction (33, 80 -82) and ER stress to neuropathic pain (77,79,83).…”

“…As DRG harbor primary sensory neurons, which are the interface of the nervous system with external and internal environments, they are crucially implicated in the beginning of somatosensory pathways including nociception (3,4,86). This, together with their accessibility, renders DRG key cellular targets for analgesic therapies (2,4,87).…”

“…Although acute pain is an evolutionary adaptive response, chronic pain is considered a pathology of the nervous system (1,2). Treatment of chronic pain presents a big challenge as current therapies target molecules with key physiological functions throughout the body resulting in minimal safety profiles.…”

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

“…As such circuitry is heavily impacted by chronic or excessive opioid exposure, further interrogation of within- and between-circuit neuroadaptations is warranted to better understand the pathological intersection of pain and addiction (Shurman et al, 2010; Cahill et al, 2016). We propose the continued use of the mechanical conflict avoidance assay for the development of novel therapeutic strategies for pain (Borsook et al, 2014). Investigations that shed light on individual differences in opioid and pain sensitivity and mesolimbic signaling may also help us maximize the beneficial use of opioid analgesics while minimizing addiction liability.…”

Genetics of chronic post-surgical pain: a crucial step toward personal pain medicine

“…This is partly because analgesic targets have been depleted. 17,18 The development of pharmacological treatment strategies for chronic pain has been largely serendipitous; pain clinicians have tried medications not initially marketed for chronic pain (e.g., antidepressants, anticonvulsants and antiarrhythmics) with mixed success. Although medications now used as first-line treatments for various chronic pain conditions (i.e., serotonin and norepinephrine re-uptake inhibitors, anticonvulsants and tricyclic antidepressants) confer some analgesic efficacy, they are not without adverse effects.…”