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.

Figure 1. Molecular and circuit architecture of pain processing.

(A) Activating the μ-opioid receptor (MOR) signaling system produces inhibitory effects on pain-initiating signal transmission but is also associated with adverse effects. See Table 1 for details. (B) Neural circuitry underlying nociceptive signal processing. Nociceptor afferents transmit signals from the periphery through the DRG to the spinal dorsal horn, where local interneurons (LINs) modulate the signals before relaying to higher-order brain structures via spinal projection neurons (SPNs). These structures include the parabrachial nucleus (PBN), periaqueductal gray (PAG), hypothalamus (HTh), thalamus (Th), prefrontal cortex (PFC), rostral anterior cingulate cortex (rACC), posterior insular cortex (PI), amygdala (Amy), and primary and secondary somatosensory cortices (S1, S2), constituting the ascending pathway (yellow). Descending pathways (blue) from the rACC, PAG, and rostral ventromedial medulla (RVM) modulate pain by inhibiting or facilitating spinal nociceptive transmission. The ventral tegmental area (VTA), nucleus accumbens (NAc), and PFC are implicated in the reward and abuse potential of opioids (red), whereas the PAG, RVM, and dorsal horn are primary sites for opioid-induced analgesia (green). (C) Peripheral tissue injury or pathogen invasion recruits immune cells that release proinflammatory cytokines, leading to heightened nociceptor excitability, which in turn drives neuropeptide release and amplifies inflammation. (D) Direct damage to nerves by injury or disease results in nociceptor hyperexcitability, demyelination, sympathetic nerve sprouting, and recruitment of peripheral immune cells to the site of injury that contribute to pain. Nonneuronal support cells secreting cytokines may exacerbate pain development. (E) Increases in ligand-gated ion channel activity, decreases in inhibitory GPCR signaling, loss of inhibitory LINs, and sprouting of nonnociceptive A fibers to the superficial dorsal horn can promote pain signaling. Recruitment of central immune cells (e.g., microglia and astrocytes) and a top-down regulation of serotonergic (5-HT), noradrenergic, and GABAergic projections via the bulbospinal tract also modulate CNS pain signals.

Figure 2. Acute and chronic pain demand distinct therapeutic strategies.

Pain can be broadly categorized into acute, subacute, and chronic phases, each defined by distinct pathophysiological mechanisms and requiring tailored therapeutic strategies. This timeline illustrates the transition from short-acting symptomatic relief to more durable, disease-modifying interventions. Acute pain, typically mediated by nociceptor activation and inflammation, is commonly managed with short-acting agents such as NSAIDs, acetaminophen, and local anesthetics. Subacute pain — often resulting from injuries with regenerative potential, such as nerve compression (neuropraxia) or crush injuries (axonotmesis) — may resolve spontaneously and can be managed with gabapentinoids, SNRIs, and physical therapy. Chronic pain, particularly under neuropathic or nociplastic conditions (see Table 2), is frequently paroxysmal and recurrent, necessitating long-lasting interventions. Current options include pharmacotherapies, surgical interventions, neuromodulation, and multimodal physical and psychological therapies, though their efficacy remains limited and variable. Emerging approaches (see Figure 4B) may offer more targeted and sustained relief. Importantly, early interventions during the acute/subacute phase may help prevent the development of maladaptive plasticity, offering a neuroprotective strategy rather than merely suppressing symptoms once chronic pain is established.

Figure 3. Drug delivery routes and techniques that enhance delivery efficacy and pharmacokinetics.

(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).

Figure 4. Current and emerging technologies for pain management.

(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).