• Rosalyn Chen, O J Michael Coppes, and Richard D Urman.
• Boston University School of Medicine, Boston, MA.
• Pain Physician. 2021 Mar 1; 24 (2): 153-163.

BackgroundAlthough conventional pain relief therapeutics have centered around mu-opioid agonists, these drugs are limited by adverse side effects, including respiratory depression and addiction potential. The ongoing opioid epidemic has galvanized research into novel analgesic therapies with more favorable profiles. New pharmacologic agents have been developed to target neuronal pathways involved in pain sensation. Certain receptors have been recognized to mediate nociceptive transmission, central sensitization, and the development of chronic pain states.ObjectivesWe conducted a literature review to identify potential targets for novel analgesic therapies.Study DesignThis study is a narrative review of potential analgesic targets. We characterize their antinociceptive mechanisms of action and evaluate their therapeutic potential.MethodsA systemized search of available literature on novel analgesics was performed. A search was performed through the PubMed database to identify articles with key words of "novel analgesics," "novel non-opioid analgesics," "novel pain targets," and "non-opioid analgesics." Potential drug classes were identified and researched through corresponding keywords, with an emphasis on publications from 2018 to 2020. Older articles were included if frequently referenced by current literature.ResultsPotential novel analgesic targets include Nav1.7, Nav1.8, CaV2.2, and transient receptor potential vanilloid-1 (TRPV1) cation channel receptors in the peripheral nervous system. Other approaches disrupt the synthesis of pronociceptive signaling molecules such as nitric oxide, prostaglandin E2, and interleukin-6 (IL-6). Within central pain pathways, modification of kappa-opioid, delta-opioid, N-methyl-D-aspartate, and cannabinoid receptors have been investigated in chronic pain and hyperalgesia models. Recent advances in molecular technology have also presented opportunities to modify protein expression or the cellular genome altogether.LimitationsSeveral analgesic targets have only demonstrated efficacy in preclinical trials. There are limited data evaluating the long-term safety profiles of therapies further on in development.ConclusionsWe provide an overview of potential analgesic therapies in various stages of development, which may become clinically relevant in the near future. Some drugs such as TRPV1 agonists, anti-IL-6, and anti-nerve growth factor antibodies have demonstrated analgesic effect in specific clinical pain states.

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