Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Abstract

Opioids Opioids 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 re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 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 drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical 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 non-addictive analgesics.

Self-Administered Skills-Based Virtual Reality Intervention for Chronic Pain: Randomized Controlled Pilot Study

“…79,80 In response to the public health crisis resulting from the current opioid epidemic, there is a surge of interest in non-opioid pharmacotherapies for chronic pain. [81][82][83] Non-opioid medications that are commonly used include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants (e.g., serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs]), anticonvulsants, musculoskeletal agents, biologics, topical analgesics and anxiolytics. [83][84][85][86] Non-opioid medications can mitigate and minimize opioid exposure.…”

Music-Enhanced Analgesia and Antiseizure Activities in Animal Models of Pain and Epilepsy: Toward Preclinical Studies Supporting Development of Digital Therapeutics and Their Combinations With Pharmaceutical Drugs

“…Further studies are required to test mechanism(s) of action of music-enhanced analgesia and antiseizure activities. (122) and mobile apps for pain (15), drug-device combination products offer seamless integration and delivery of two modes of action simultaneously. This paradigm is further illustrated in Table 3 and Figure 9.…”

Lessons for Better Pain Management in the Future: Learning from the Past

“…Effective pain management for chronic pain is achieved through a patient-centered, multidisciplinary approach that may include pharmacotherapy including opioid and non-opioid options [ 1 ]. However, due to the opioid epidemic and the public care crisis, there is a surge of interest in non-opioid pharmacotherapies for chronic pain, while continuing with the research to best opioid therapy [ 105 , 107 , 108 ]. Non-opioid medications that are commonly used include acetaminophen, non-steroidal anti-inflammatory (NSAIDS), antidepressants, anticonvulsants, musculoskeletal agents, biologics, topical analgesics, and anxiolytics [ 1 ].…”