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 3

Drug delivery routes and techniques that enhance delivery efficacy and pharmacokinetics.

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Drug delivery routes and techniques that enhance delivery efficacy and p...
(A) Oral administration is most common but suffers from first-pass metabolism and limited CNS penetration. Intranasal delivery offers rapid absorption via the olfactory and trigeminal pathways, enhancing brain access. Parenteral routes, including subcutaneous, intramuscular, and intravenous injections, provide faster onset but with systemic exposure and potential side effects. For localized pain control, topical and transdermal patch formulations minimize systemic effects while allowing sustained drug release. Sonophoresis enhances transdermal penetration using ultrasound waves (187). Intrathecal and intracerebroventricular delivery bypass the blood–cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB), allowing direct access to the cerebrospinal fluid (CSF). Intraganglionic administration is an effective route as the DRG is a primary site for the initiation of pain triggering signals and lies outside the BCSFB (188). Implantable systems, including silicone polymer–based depots and osmotic pumps, enable controlled, long-term drug release (189). (B) Biodegradable hydrogels offer sustained drug release, providing localized delivery with minimal systemic side effects (190). These hydrophilic networks respond to environmental triggers such as pH or temperature to control drug release (191). Nanoparticles, including lipid-based, polymeric, and inorganic variants, improve drug solubility, stability, and targeted tissue penetration while overcoming biological barriers (192). Engineered microneedles enable painless, transdermal drug delivery, bypassing the stratum corneum, improving bioavailability for molecules and biologics (193). Nanorobots, driven by magnetic, light, acoustic, or chemical propulsion, hold promise for precision-targeted drug delivery, actively navigating biological environments to reach specific tissues (194). There is also a targeted pain-specific local analgesia strategy involving coadministration of membrane-impermeant sodium channel blockers such as QX-314 or BW-031 with agonists that activate large-pore channels selectively expressed in nociceptors (e.g., capsaicin-TRPV1). This approach facilitates drug entry only into nociceptors, effectively blocking their activity while preserving motor and tactile function (195, 196).