Mechanism-based nonopioid analgesic targets
Xiangsunze Zeng, Rasheen Powell, Clifford J. Woolf
Xiangsunze Zeng, Rasheen Powell, Clifford J. Woolf
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Review

Mechanism-based nonopioid analgesic targets

Abstract

Acute pain management has historically been dominated by opioids, whose efficacy is overshadowed by the risks of addiction, tolerance, and dependence, culminating in the global opioid crisis. To transcend this issue, we must innovate beyond opioid-based μ receptor treatments, identifying nonopioid analgesics with high efficacy and minimal adverse effects. This Review navigates the multifaceted landscape of inflammatory, neuropathic, and nociplastic pain, emphasizing mechanism-based analgesic targets tailored to specific pain conditions. We delve into the challenges and breakthroughs in clinical trials targeting ion channels, GPCRs, and other molecular targets. We also highlight the intricate crosstalk between different physiological systems and the need for multimodal interventions with distinct pharmacodynamics to manage acute and chronic pain, respectively. Furthermore, we explore emerging strategies, including gene therapy, stem cell therapy, cell type–specific neuromodulation, and AI-driven techniques for objective, unbiased pain assessment and research. These innovative approaches are poised to revolutionize pain management, paving the way for the discovery of safer and more effective analgesics.

Authors

Xiangsunze Zeng, Rasheen Powell, Clifford J. Woolf

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Figure 4

Current and emerging technologies for pain management.

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Current and emerging technologies for pain management. (A) Traditional a...
(A) Traditional approaches encompass pharmacotherapy, physical therapy (manual therapy, cryo-/thermotherapy), psychotherapy, surgery, and electrical neuromodulation, which are selected based on specific pain conditions. Physical and psychological (cognitive-behavioral therapy) therapies are often recommended for conditions resistant to conventional pharmacotherapy, like fibromyalgia (26). Surgical excision may address structural pain sources such as neuromas (197). Neuromodulation is typically reserved for refractory chronic pain unresponsive to standard treatments (198). In practice, multimodal approaches combining several strategies are common. (B) Emerging approaches aim to offer tailored, mechanism-based pain relief. CRISPR delivered through an adeno-associated virus (AAV) or nanoparticle allows precise editing of “pain genes” at the DNA level for permanent effects. Antisense oligonucleotides (ASOs) are short, single-stranded DNA or RNA strands that bind to specific mRNA transcripts, either degrading them via RNase H–mediated cleavage or blocking their translation, thereby transiently preventing production of pain-related proteins. Stem cell therapy using mesenchymal stem cells (MSCs) promotes tissue repair and reduces inflammation by secreting neurotrophic factors (NGF, GDNF, BDNF) and antiinflammatory cytokines (IL-10, TGF-β). MSC-derived exosomes may also serve as natural nanocarriers for delivering drugs or siRNAs (199). Patient-derived induced pluripotent stem cells (iPSCs) can be differentiated into DRG neurons and Schwann cells to repair or replace damaged tissues. Advanced neuromodulation leverages cell-specific genetic tools. Optogenetics can directly modulate neuronal activity with various opsins responsive to light of different wavelengths, inducing excitatory (ChR2) or inhibitory (GtACR1 or NpHR) effects. Sonogenetics couples ultrasound stimulation with mechanosensitive channels such as TRP-4, offering noninvasive deep tissue neuromodulation. Humanized PSAM4-GlyR chemogenetics using an FDA-approved agonist offers translational promise. AI/ML techniques not only enable automated unbiased analysis of pain behaviors, neuroimages, neural activity, and omics integration, but also advance drug discovery, and the modeling of cellular and circuit pain processes via AI-powered virtual cells (AIVCs). Finally, virtual reality that engages sensory and cognitive pathways can be an adjunctive therapy for certain chronic pain (200), like complex regional pain syndrome (CRPS) (ClinicalTrials.gov NCT04849897).