• Nebojsa Nick Knezevic, Ajay Yekkirala, and Tony L Yaksh.
• From the *Department of Anesthesiology, Advocate Illinois Masonic Medical Center Chicago, Illinois; Departments of †Anesthesiology and ‡Surgery, University of Illinois, Chicago, Illinois; §Department of Neurobiology, Harvard Medical School, and Boston Children's Hospital, Boston, Massachusetts; ‖Blue Therapeutics, Harvard Innovation Launch Lab, Allston, Massachusetts; and Departments of ¶Anesthesiology and #Pharmacology, University of California, San Diego, La Jolla, California.
• Anesth. Analg. 2017 Nov 1; 125 (5): 171417321714-1732.

AbstractOpioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

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