Emerging pharmacological strategies for neuropathic pain: Mechanism-based targeting and precision medicine

Neuropathic pain (NP) is a common chronic pain condition caused by a lesion or disease affecting the somatosensory nervous system and is clinically characterized by ongoing or intermittent spontaneous pain, often accompanied by allodynia and hyperalgesia. It can arise from a wide range of conditions, including diabetic neuropathy, postherpetic neuralgia (PHN), spinal cord injury (SCI), and chemotherapy-induced neurotoxicity, and is associated with substantial impairment in quality of life [1]. Epidemiological studies further highlight the considerable population-level burden of NP. In a survey of 24,925 individuals, 63.7% reported experiencing pain, and 15.7% (95% CI: 14.9%-16.5%) of those with pain met PainDETECT-based criteria for probable NP, corresponding to an estimated overall prevalence of approximately 10% (95% CI: 9.5%–10.5%) [2]. The prevalence of NP also appears to vary across racial and ethnic groups, with higher rates reported among Black and Hispanic populations than among White populations. Despite this substantial clinical burden, current management remains largely symptom-oriented and commonly involves gabapentinoids and antidepressants as first-line therapies, with topical agents and opioid-based therapies used in selected or refractory cases [3].

NP differs from predominantly nociceptive or inflammatory pain in its tendency to persist after nervous system injury and in the marked interindividual variability in treatment response. Its development and maintenance involve complex interactions among maladaptive neuronal plasticity, neuroinflammatory activation, neurotransmitter dysregulation, and altered pain-processing networks [1]. For example, SCI has been reported to increase neuronal activity in several nociception-related regions, including the NTM/NPL regions (GrN and PBN), while increasing GAD67 expression in the periaqueductal gray (PAG), reducing serotonin levels in the raphe magnus nucleus (RMN), and suppressing NTR2-expressing fear-inhibitory neurons in the basolateral amygdala (BLA). SCI-induced alterations in hippocampal neurogenesis may further contribute to the persistence and amplification of maladaptive pain processing [4]. Collectively, these neuroplastic and neurochemical changes create a pathological environment that facilitates persistent nociceptive signalling and chronic pain. Advances in our understanding of NP pathophysiology have been accompanied by increasing efforts to identify novel pharmacological targets. In several rodent models of NP, compounds 50a and 56a have shown significant analgesic activity against oxaliplatin- and paclitaxel-induced neuropathy as well as streptozotocin-induced diabetic NP, with compound 56a exhibiting the strongest in vivo effects [5]. In addition, BDNF-mediated regulation of KCC2 expression in dorsal root ganglia (DRG) has been implicated in peripheral and central sensitization and may contribute to the attenuation of bisphenol A (BPA)-induced NP [6]. These findings illustrate how mechanistic studies can identify potential therapeutic targets and provide a rationale for the development of mechanism-based analgesic strategies.

Nevertheless, NP is still predominantly treated using conventional pharmacological and neuromodulatory agents, including gabapentinoids and antidepressants as first-line therapies, with topical agents and opioid-based therapies used in selected or refractory cases. Although these therapies can provide symptomatic relief, their overall efficacy is often modest, adverse effects remain common, and treatment responses vary substantially among patients [3]. Despite considerable progress in elucidating the molecular mechanisms underlying the development and persistence of NP, translating these discoveries into clinically effective therapies remains challenging. Numerous molecular targets have demonstrated promising analgesic effects in preclinical models, yet relatively few have achieved successful clinical translation. This translational gap likely reflects several factors, including the limited ability of experimental models to reproduce the phenotypic heterogeneity of human NP, insufficient target specificity, the lack of validated predictive biomarkers, and substantial interpatient variability. As understanding of NP biology continues to evolve, therapeutic development is progressively shifting from symptom-oriented management toward mechanism-based interventions targeting neuroinflammation, ion-channel dysfunction, synaptic plasticity, and neuroimmune interactions. At the same time, advances in precision medicine and pharmacogenomics are creating new opportunities for individualized treatment selection and optimization. In this Review, we summarize the major biological mechanisms underlying NP, discuss conventional and emerging pharmacological approaches, critically examine the translational barriers limiting the clinical success of mechanism-based therapies, and highlight future opportunities for biomarker-guided and precision-oriented pain management.

2.1 Neuronal plasticity and pain signal transduction

NP is a chronic pain condition caused by injury or dysfunction of the nervous system and can arise as a consequence of trauma, inflammation or peripheral nerve damage. NP is a multifactorial condition involving a complex network of pathological changes occurring in both the peripheral and central nervous systems. In this context, maladaptive neuronal plasticity and remodelling of pain-associated signalling processes emerge as essential factors in the establishment and maintenance of chronic pain. Trans-synaptic autophagy has been recently identified as an important regulatory process involved in chronic pain states [7]. In terms of synaptic organization and neuronal function, autophagic removal of damaged cellular components at local compartments modulates both processing and transmission of nociceptive signals [7]. Nevertheless, dysregulation or excessive activation of this process may lead to abnormal remodelling of neural circuits that enhance nociceptive signalling, resulting in heightened pain sensitivity and the persistence of pathological pain [8].

The spinal cord acts as a central regulatory hub both to initiate and maintain NP. In addition to serving as a relay for peripheral nociceptive signals, the spinal cord also plays an active role in central sensitization and the development of chronic pain states. Activation of spinal neurons and glial cells following peripheral nerve injury or intrinsic spinal stress signals leads to significant alterations in neuronal excitability and synaptic plasticity [9]. The coordinated interactions between neurons and glial cells in the spinal cord are crucial for developing and maintaining central sensitization. Microglia can also affect astrocytic activity and disturb synaptic glutamate clearance, resulting in the activation of extrasynaptic NMDARs, increased aberrant neuronal excitability, and enhanced aberrant synaptic transmission as well as neural network remodelling [10]. Meanwhile, miR-146a-5p regulates the balance of microglial autophagy and pyroptosis through TRAF6 targeting [11]. These neuro–glial interactions play a pivotal role in synaptic dysfunction and the persistence of pain signalling.

Advances in mechanistic understanding have led to the identification of emerging molecular pathways and therapeutic targets. GRID1/GluD1-dependent trans-synaptic autophagy has been implicated in synaptic regulation associated with chronic pain, and its dysfunction induces abnormal pain phenotypes, underscoring its role in pain maintenance [7]. In addition, NMDA receptor–associated nitric oxide signalling is a key regulator of spinal nociceptive transmission. Eukaryotic elongation factor 2 kinase (eEF2K) modulates L-arginine utilization and participates in NMDA-dependent nitric oxide signalling, thereby influencing neuronal excitability and synaptic transmission [12]. Following peripheral nerve injury, microglial activation and pyroptosis, impaired astrocytic glutamate uptake, dysregulated trans-synaptic autophagy and enhanced NMDA receptor signalling are functionally coupled, collectively driving spinal synaptic plasticity remodelling and sustained amplification of nociceptive signalling as shown in Figure 1. Targeting NMDA receptor–related signalling networks may therefore provide novel molecular strategies for therapeutic intervention.

Overall, NP is characterized by increased neuronal excitability, aberrant nociceptive signalling, and remodelling of spinal neural circuits. Trans-synaptic autophagy plays a critical role in regulating synaptic structure and neuronal activity during the development and maintenance of chronic pain, whereas excessive microglial activation exacerbates neuroinflammation and sustains pain signalling. These central plasticity mechanisms provide a foundation for further exploration of inflammation-driven pain processes.

2.2 Inflammation-driven mechanisms of NP

Neuroinflammation is a key driver of the development and persistence of NP. In particular, activation of microglia and astrocytes enhances nociceptive signalling through the release of pro-inflammatory cytokines and chemokines, thereby increasing pain sensitivity and promoting chronicity.

Metabolic reprogramming, especially enhanced glycolysis, plays a central role in sustaining neuroinflammatory responses in neuropathic pain. Activated microglia undergo metabolic reprogramming characterized by a shift from oxidative phosphorylation toward enhanced glycolysis, which promotes pro-inflammatory signalling, supports sustained neuroinflammatory responses, and contributes to pain sensitization and persistence [13]. Given the important role of glial cells and glycometabolism reprogramming in neuropathic pain, targeting glial cells and their metabolic regulation has emerged as a potential therapeutic strategy [13]. For instance, semaglutide (SEMA) has been reported to exert neuroprotective effects in diabetic NP by inhibiting astrocytic and microglial activation, thereby alleviating inflammation and oxidative stress [14]. Furthermore, PRMT6 interacts with HIF-1α to promote the stabilization of glycolytic processes, subsequently enhancing neuroinflammation and facilitating pain progression, suggesting its potential as a therapeutic target [15].

Beyond glycolytic regulation, accumulating evidence indicates that additional molecular regulators participate in the control of neuroinflammatory responses. TRIM28 has been implicated in NP pathogenesis by modulating microglial function and regulating autophagy and ferroptosis, suggesting a previously unrecognized mechanistic link involved in pain development [16]. In addition, ozone has been reported to alleviate neuroinflammation through activation of the p-AMPK/Gas6/MerTK/SOCS3 signalling axis, thereby enhancing macrophage clearance, with preliminary findings indicating its potential clinical relevance [17]. Collectively, glial activation and the production of pro-inflammatory mediators represent key contributors to aberrant pain signalling, whereas glycolytic reprogramming and associated pathways not only support the metabolic requirements of inflammatory processes but also reveal potential therapeutic targets. Modulating these mechanisms may facilitate the development of more precise and individualized therapeutic strategies for NP and provide new opportunities for future drug discovery.

2.3 Neurotransmitter imbalance and pain perception

In addition to neuroinflammatory processes and glial cell-mediated regulation, disruption of neurotransmitter homeostasis represents another fundamental mechanism contributing to NP development. Disruption of the balance between excitatory and inhibitory neurotransmission is considered an important contributor to abnormal pain processing in NP. This imbalance promotes neuronal hyperexcitability and leads to sustained amplification of nociceptive signalling. Among the major inhibitory neurotransmitter systems, γ-aminobutyric acid (GABA) and glycine are pivotal for ensuring efficient inhibitory circuits. Under physiological conditions, GABA prevents excessive neuronal activation via receptor-mediated signalling to reduce nociceptive transmission. However, impaired GABAergic function is common in NP. Following neuronal injury or circuit disruption, reduced GABA release and diminished receptor responsiveness may weaken inhibitory regulation, allowing sustained nociceptive signalling and persistent pain perception [18]. Simultaneously, maladaptive reorganization of local neural circuits (synaptic restructuring and upregulation or downregulation of pain-related pathways) contributes to the amplification of nociceptive inputs. Thus, perturbing excitatory–inhibitory balance not only increases local pain processing, but can also increase the spread of hypersensitivity across regions beyond the initial site of injury.

The spinal cord serves as a key integration centre for nociceptive information processing. After neural injury or pathological changes, spinal neurons can develop spontaneous hyperexcitability, generating persistent nociceptive activity. At the same time, neuroinflammatory responses promote the release of excitatory neurotransmitters and further increase neuronal responsiveness, thereby sustaining abnormal pain signalling. Multiple molecular pathways participate in this process. For example, the α2δ-1 subunit, metabotropic glutamate receptor 5 (mGluR5), and NMDA receptor signalling pathways have been implicated in spinal disinhibition and nociceptive hypersensitivity following injury. These molecular changes collectively contribute to the establishment of a dysregulated neurotransmitter network that supports NP development and maintenance. Given the central role of excitatory–inhibitory imbalance in NP, restoring inhibitory neurotransmission has become an important therapeutic direction. Strategies that enhance KCC2 function can help re-establish inhibitory control in the central nervous system (CNS), thereby correcting excitation–inhibition (E/I) imbalance and reducing pathological pain [19]. In addition, botulinum toxin A has been reported to relieve chronic sciatic pain through modulation of SNAP-25 expression [20]. Therapeutic approaches designed according to specific pathological mechanisms may provide additional opportunities to restore coordination between excitatory and inhibitory networks and achieve more effective pain control.

In summary, impaired inhibition and neurotransmitter imbalance are core mechanisms underlying NP pathogenesis. Sustained and inappropriate excitation/inhibition imbalance drives pain hypersensitivity, whereas keeping a proper equilibrium of excitatory vs inhibitory signalling is critical for normal pain processing. Better characterization of these mechanisms may enable the design of more mechanistically-principled and personalized strategies aimed at re-establishing E/I balance and enhancing NP management.

3.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs exert their analgesic and anti-inflammatory effects mainly through inhibition of cyclooxygenase (COX)-dependent prostaglandin synthesis. Although these agents are widely used in inflammation-related pain conditions, their effectiveness in NP is generally limited. Increasing evidence suggests that NSAIDs may also influence pain processing beyond classical suppression of inflammation through mechanisms involving lipid mediators and metabolic regulation. For instance, aspirin-triggered lipoxin A4 decreases NP-like behaviours and anxiety-related responses in diabetic rats, while simultaneous administration with cannabinoid receptor agonists produces greater analgesic effects than either treatment alone [21]. In addition, short-term treatment with diclofenac was found to reduce sensory dysfunction associated with NP, which may be mediated by modulation of the kynurenine pathway, including increases in KYNA levels and an increased KYNA/QA ratio. Such effects may be due to modulation of glutamatergic neurotransmission and pathways involved in excitotoxicity [22]. Consequently, NSAIDs may represent more than just inhibitors of inflammatory responses in NP, and may regulate peripheral sensitization, central sensitization, and descending pain inhibitory pathways (Figure 2).

NSAIDs have shown minimal but clinically relevant effects in many NP-related clinical conditions, especially in sciatica. Sciatica is a common condition caused by nerve root compression associated with local inflammatory responses triggered by intervertebral disc herniation or degenerative changes of the spine, manifesting as radiating pain along the sciatic nerve distribution. NSAIDs may partially attenuate nociceptive transmission and pain perception by reducing local inflammation and peripheral sensitization [23]. Yet, in a clinical context, patients with acute low back pain or sciatica treated with NSAIDs (either alone or in conjunction with other analgesic medications) do not show major improvements in functional recovery [24]. This observation indicates that the therapeutic effect of NSAIDs may be partly dependent on disease-related characteristics and patient-specific factors. Importantly, sciatica encompasses heterogeneous spine-related leg pain conditions with differing dominant pain characteristics, including nociceptive and neuropathic components, rather than representing a uniformly classical neuropathic pain condition [25, 26]. Thus, the clinical efficacy of NSAIDs in sciatica is primarily likely mediated by inhibition of peripheral inflammatory pathways rather than direct alteration of neuropathic mechanisms. This further highlights that the relatively modest effects of systemic anti-inflammatory agents in classical NP suggest that simple modulation of inflammation is insufficient to overcome the multiple redundant neuronal and neuroimmune alterations involved in chronic NP [1, 27].

NSAIDs have a long history of analgesic efficacy, but chronic use warrants safety concerns. Gastrointestinal complications (e.g., mucosal injury, ulcer development, and bleeding) are common but serious adverse events associated with prolonged exposure or high-dose use, especially in elderly individuals. NSAIDs may additionally adversely affect renal function and increase cardiovascular risk, especially among patients with existing disease states predisposing to these outcomes [28]. Consequently, NSAID treatment should be guided by individualized risk stratification that considers medication type, dosage, and duration of therapy. NSAIDs are often used in conjunction with other non-opioid analgesics or neuromodulatory agents (antidepressants and anticonvulsants) to overcome the limitations of NSAID monotherapy and increase analgesic efficacy. These multimodal strategies could act by modulating pain pathways regulated through different molecular targets, possibly improving analgesic efficacy and neuropathic symptoms [29]. However, in patients with moderate-to-severe NP or inadequate responses to NSAIDs, anti-inflammatory analgesia alone is often insufficient and may require treatment escalation to agents that act through different mechanistic pathways, such as opioids.

3.2 Opioids: Efficacy and risks

Opioids are still an important class of drugs for NP, especially in cases of moderate to severe pain or inadequate response to first-line treatments. The majority of their analgesic effects are mediated through the activation of μ-opioid receptors, which suppress the transmission of nociceptive signals. In addition to central actions, peripheral μ-opioid receptor activation may further modulate pain processing through the regulation of transient receptor potential (TRP) channels and voltage-gated sodium channels, as well as decreasing nitric oxide-associated stress responses and neuroinflammatory activity. These interactions likely contribute to analgesic effects at the molecular level [30].

Various formulations of opioids have been investigated across multiple NP conditions. Tramadol-based combinations have shown favourable efficacy and tolerability in managing patients suffering from PHN; for example, extended-release tramadol combined with an immediate-release formulation has demonstrated efficacy in reducing pain intensity while improving quality of life [31]. Tapentadol has been investigated as a treatment option for patients with cancer-related NP who do not respond adequately to conventional opioid therapy, providing analgesic benefits with a relatively favourable safety profile [32]. Methadone has also been used as an adjunctive therapy in specific clinical scenarios, in which improvements in sleep quality and other functional outcomes may be achieved [33].

Recent developments in our knowledge of the mechanisms of NP have additionally encouraged increased opportunities for personalized pain treatment with opioids. For example, the combination of morphine and FLT3 inhibitors has been shown to retain analgesic efficacy while decreasing side effects related to opioid dosage escalation, highlighting the value of incorporating mechanism-based approaches in clinical practice [34]. These results provide further information on how opioid-based therapies may be optimized in clinical practice.

Although long-term opioid treatment has shown clinical utility, it is not without important drawbacks, notably tolerance, dependence, and a variety of other side effects. Individualized treatment decisions should incorporate consideration of both pain phenotype and underlying disease characteristics, as well as patient tolerance, in order to find the optimal balance between analgesia and safety. Combination strategies using neuromodulatory agents, specifically antidepressants and anticonvulsants, to improve long-term NP management have received increasing interest in this setting.

Another major concern during prolonged opioid therapy is opioid-induced hyperalgesia (OIH), which represents a paradoxical increase in pain sensitivity after exposure to opioids. Clinically, differentiation of OIH from disease progression, opioid tolerance, or inadequate pain control can be difficult. Signs of OIH include worsening pain despite escalating doses of opioids, increased sensitivity to pain (hyperalgesia), decreased analgesic effects from the same opioid dose, and relief after decreasing the opioid dose or rotating to another opioid [35, 36]. The proposed mechanisms underlying OIH involve enhanced glutamatergic signalling, NMDA receptor activation, neuroinflammatory responses, and central sensitization, which collectively contribute to increased nociceptive processing [35, 37]. Several therapeutic strategies, including opioid dose adjustment, opioid rotation, NMDA receptor modulation using low-dose ketamine, and partial opioid receptor agonists, have been explored; however, their clinical effectiveness remains to be fully established [36, 37].

3.3 Antidepressants and antiepileptic drugs in pain management

NP is a chronic pain condition caused by injury or dysfunction of the nervous system and is characterized by persistent or intermittent pain, limited responsiveness to conventional analgesics, and frequent co-occurrence with affective disorders, including anxiety and depression. Its pathogenesis involves complex alterations in neuronal plasticity, neuroinflammatory regulation, and neurotransmitter homeostasis, among which monoaminergic signalling pathways play an important regulatory role. Descending inhibitory pathways mediated by serotonin and noradrenaline represent essential modulatory systems involved in the control of nociceptive processing. Accordingly, antidepressants may exert therapeutic benefits in NP through both mood-related and analgesic mechanisms. At the molecular level, these agents exert analgesic effects by strengthening descending inhibitory pathways and modulating neuroinflammatory responses. For example, paroxetine has been reported to attenuate chronic NP through the regulation of multiple pain-associated proteins [38]. In addition, low-dose esketamine has been shown to alleviate depression-like behaviours associated with NP, possibly through modulation of the Homer1a–mGluR5 signalling pathway [39].

In clinical practice, combining antidepressants with antiepileptic drugs has become an important therapeutic approach for NP management. Antiepileptic agents, particularly gabapentin and pregabalin, primarily reduce neuronal hyperexcitability by targeting voltage-gated calcium channel α2δ subunits or stabilizing neuronal membrane function, thereby limiting abnormal neuronal firing and reducing pain transmission. By contrast, antidepressants act mainly through inhibition of neurotransmitter reuptake, enhancing serotonergic and noradrenergic signalling and modulating multiple pain-related pathways. Clinical studies have indicated that fixed-dose combinations (FDCs) of low-dose pregabalin and duloxetine can achieve analgesic effects comparable to high-dose pregabalin monotherapy while maintaining an acceptable safety profile. Dizziness and somnolence remain the most commonly reported adverse events [40]. Furthermore, trazodone administered at doses of 50–100 mg has been reported to enhance the analgesic effects of gabapentin, providing additional support for low-dose combination strategies in NP treatment [41].

Recently, novel antidepressants have gained attention for their potential role in NP treatment. Venlafaxine exerts multimodal effects through the modulation of multiple neurotransmitter receptors and signalling pathways, including α2-adrenergic receptors, 5-HT3 and 5-HT1B/1D receptors, cholinergic pathways, as well as CB1/CB2 cannabinoid and adenosine A1 receptors [42]. In preclinical models, venlafaxine has been shown to attenuate oxaliplatin-induced NP and mechanical allodynia, with α2-adrenergic and 5-HT3 receptors contributing to distinct pain modalities [42]. In addition, antidepressants have been shown to demonstrate analgesic effects in trigeminal neuralgia (TN), visceral pain and inflammatory pain models, with relatively mild adverse effects, including nausea, dry mouth and sleep disturbances [43].

Overall, antidepressants and antiepileptic drugs play a central role in the long-term management of NP by modulating neurotransmitter systems and neuronal excitability. However, conventional pharmacotherapy remains limited by interindividual variability in efficacy and adverse effects, with mechanisms largely confined to neurotransmitter regulation. With increasing recognition of the role of neuroinflammation in pain maintenance and amplification, therapeutic strategies targeting neuroinflammatory pathways are emerging as a major focus of research. A summary of representative agents, mechanisms of action and clinical applications of antidepressants and antiepileptic drugs in NP is provided in Table 1.

4.1 Targeting neuroinflammation

Neuroinflammation is a central mechanism underlying the initiation and persistence of NP. Following peripheral nerve injury, activation of glial and immune cells leads to the release of pro-inflammatory mediators, including TNF-α, IL-1β, and IL-6, which enhance neuronal excitability and amplify nociceptive signalling through neuroimmune interactions, thereby promoting central sensitization and pain chronicity. Consequently, targeting neuroinflammatory pathways has emerged as a major therapeutic strategy.

Within neuroinflammatory regulation, glial polarization states play a critical role in pain modulation. Emerging evidence indicates that active components of DHJSD may attenuate neuroinflammation by regulating microglial M1 polarization, potentially via Peroxisome proliferator-activated receptor-γ (PPARG)–dependent mechanisms [80]. In addition, the double-stranded RNA–induced Toll-like receptor 3 (dsRNA–TLR3) signalling pathway has been implicated in both neuroinflammation and the development of morphine tolerance, suggesting that targeting this pathway may provide a therapeutic approach to mitigate opioid tolerance [81]. Inter-glial immune signalling also represents a promising avenue for intervention. For example, intrathecal administration of the CD200R1 agonist CD200Fc rapidly suppresses glia-associated neuroinflammatory responses and effectively alleviates NP, highlighting its potential as a novel therapeutic modality [82].

Advances in molecular biology have revealed a growing number of inflammatory signalling pathways that contribute to NP pathogenesis. Among these, the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway, a critical component of innate immune sensing, has emerged as an important regulator of neuroinflammation and a potential therapeutic target for NP [83]. Similarly, signal transducer and activator of transcription 3 (STAT3) acts as a key molecular regulator in NP by influencing glial polarization and the expression of inflammatory mediators. Pharmacological inhibition of STAT3 signalling using Bt354 has been reported to suppress inflammatory responses and reduce pain behaviours, supporting its potential therapeutic value [84]. These findings highlight emerging molecular targets for the development of more precise anti-inflammatory analgesic approaches. Following peripheral nerve injury, the activation of neuroinflammatory cells and the disruption of multiple signalling networks interact to promote the initiation and persistence of NP. The major mechanisms and corresponding therapeutic targets are summarized in Figure 3.

In addition to upstream signalling pathways, therapeutic strategies targeting inflammatory mediators and downstream effectors have also attracted increasing attention. For example, NR-3 has been shown to increase mechanical and thermal pain thresholds in spinal nerve ligation (SNL) models without altering baseline nociception in healthy animals, suggesting a favourable degree of therapeutic selectivity. Its analgesic effects are likely mediated through inhibition of the MMP2/IL-1β signalling axis in the DRG and spinal astrocytes, thereby attenuating neuroinflammation and reducing persistent pain states [85]. Overall, continued advances in our understanding of neuroinflammation and neuroimmune interactions are accelerating the development of therapies targeting inflammatory mediators and related signalling pathways. These approaches provide important mechanistic insights into NP treatment and may contribute to the future development of more targeted and individualized therapeutic strategies.

4.2 Stem cell therapy and regenerative medicine

Stem cell-based therapies have attracted growing attention in NP research because of their potential immunomodulatory, neuroprotective, and regenerative effects. Among these approaches, mesenchymal stem cells (MSCs), including human umbilical cord-derived MSCs (HUC-MSCs), have shown analgesic potential in preclinical models. Their beneficial effects are thought to involve multiple mechanisms, including regulation of neuroinflammatory responses, modulation of glial activation, secretion of neurotrophic factors, and restoration of the injured neural microenvironment [86, 87]. In addition, transplantation of neural stem/progenitor cells has demonstrated therapeutic effects in experimental models of nerve injury and spinal cord injury (SCI), possibly through promoting neural repair processes and reducing pain sensitization [88, 89].

In addition to direct cellular transplantation, cell-free strategies based on extracellular vesicles, particularly MSC-derived exosomes, have enhanced the potential applications of regenerative therapies. Experimental studies suggest that exosomes can influence a range of pathological processes relevant to NP, including inflammatory regulation, synaptic plasticity, remyelination, and neuronal survival. Compared with cell-based therapies, exosome-based therapeutic approaches may offer some advantages, such as lower immunogenicity and improved biosafety profiles [90]. Despite encouraging evidence in preclinical studies, clinical translation of stem cell-based therapies for NP remains limited. The current evidence is mainly based on animal models of peripheral nerve injury or SCI, and high-quality randomized controlled trials in patients with NP are still lacking. Ultimately, a wide range of translational challenges need to be addressed, including variability in cell sources, manufacturing processes, administration routes, dosing regimens, quality control procedures, and long-term safety assessment [91-94]. Thus, stem cell-based therapies should currently be viewed as investigational rather than established NP treatment modalities. Future studies will need to focus on improving manufacturing standardization, identifying biomarker-defined patient populations most likely to respond, and conducting rigorously designed clinical trials using clinically meaningful outcomes.

4.3 Rational combination strategies and multi-target pharmacotherapy

Single-target therapeutic strategies in NP remain insufficient and are unlikely to fully address the heterogeneous mechanisms underlying disease, such as neuronal hyperexcitability, neuroinflammatory activation, and central sensitization. This has led to the development of combination approaches, where small molecules and biologic agents are administered together since such strategies may provide complementary benefits in terms of tissue penetration, onset of action, and target specificity, potentially allowing intervention at multiple pathological processes.

Biologic therapies directed at neuroinflammatory pathways represent one area of growing interest. Astrocyte senescence has been suggested to contribute significantly to neuroinflammatory responses after peripheral nerve injury, and targeting astrocytic activation states or related secreted molecules, such as clusterin (CLU), may represent a potential therapeutic strategy [95]. Similarly, nerve growth factor (NGF) is an important regulator of pain sensitivity and is involved in several pain-associated conditions. NGF silencing has been reported to influence nociceptive signalling pathways and may improve the efficacy of immunochemotherapy while supporting relatively low-toxicity delivery approaches [96]. Together, these findings suggest that selective regulation of inflammatory mediators and neurotrophic factors may provide opportunities to intervene in neuroinflammatory processes involved in NP.

Because of the potential complementary effects between different agents, a mechanistic aspect of combination therapies is that they may produce effects unattainable with single-agent treatment. Small molecules usually allow rapid modulation of neuronal activity, whereas biologic agents may have a more prolonged effect on the regulation of inflammatory and immune processes. For instance, ambroxol, a small-molecule ion channel modulator, inhibits Nav1.8 and can additionally influence TRPV1 and TRPA1 channels at higher concentrations, indicating a relatively wide modulatory profile [97]. Such features may support the rationale for combining ion channel modulators with anti-inflammatory biologics. Furthermore, data from immunomodulatory studies suggest that multi-pathway interventions may enhance analgesic responses through regulation of cytokine networks, including enhancement of IL-10 expression and suppression of chemokine signalling pathways [98, 99]. In clinical practice, combination therapy is usually used when monotherapy does not offer adequate analgesia or if dose escalation is limited due to adverse effects. However, the evidence for specific mechanism-based combinations remains limited. Current clinical recommendations remain focused on rational first-line drug selection, patient-tailored dose optimisation and ongoing assessment of treatment efficacy and tolerability whilst minimising the risk of polypharmacy [100]. Combination approaches may provide advantages for selected patient populations, yet few clinical trials have defined a standard regimen applicable to NP. These combinations will also need to be based on biological mechanisms, pain phenotypes, and individual patient characteristics as opposed to simply empirical drug combinations [100, 101].

The incorporation of nanodelivery platforms has further expanded the potential of combined small-molecule and biologic therapies. Different nanocarriers offer unique advantages in central nervous system targeting and the coordinated delivery of multiple therapeutic cargos. For instance, 46.1-Lipo liposomes markedly increase brain-specific accumulation of pralidoxime, achieving approximately a tenfold enhancement in targeting efficiency [102]. Similarly, liposomal co-delivery of donepezil, memantine, and BACE-1 siRNA has been shown to reduce β-amyloid levels and related gene expression while suppressing inflammatory responses, illustrating the potential of multi-target therapeutic regulation [103]. Furthermore, lipid nanoparticles enable mRNA transport across the blood–brain barrier into the central nervous system, whereas Tan IIA-based nanoparticles promote neuroprotection and regeneration by modulating neural stem cell differentiation and neuroimmune responses [104, 105]. Collectively, nanocarrier-mediated combination strategies enable coordinated intervention at molecular, cellular, and tissue levels, providing an integrated framework for future NP therapy. Meanwhile, increasing recognition of interindividual genetic differences in drug responses highlights the potential importance of pharmacogenomics in precision treatment strategies. Despite rapid progress in nanotechnology, no nanoparticle-based formulation has been approved specifically for NP treatment by the FDA or other major regulatory agencies to date. Currently available nanomedicines are primarily applied in oncology, infectious diseases, and nucleic acid delivery, including liposomal systems, polymeric nanoparticles, and lipid nanoparticle-based platforms [106, 107]. Therefore, nanocarrier applications in NP remain an emerging area of investigation rather than an established clinical approach. Major translational challenges include achieving selective targeting within the nervous system, accurately predicting in vivo biodistribution, establishing scalable manufacturing processes, defining regulatory requirements, and demonstrating long-term safety [100, 108].

5.1 Genetic determinants of drug response

In neuropathic and other chronic pain conditions, marked interindividual differences are observed in both analgesic efficacy and treatment-related adverse effects. Pharmacogenomic studies have shown that genetic variants of drug-metabolizing enzymes, key transporters involved in drug transport, and target proteins can influence clinical responses to therapy and susceptibility to toxicity. Thus, elucidating the genetic factors underlying interindividual differences in analgesic responses has become an integral part of precision medicine for pain treatment. Importantly, beyond single loci, the genetic determinants of treatment response span multiple biological levels, including pain processing, pharmacokinetics, pharmacodynamics and clinical outcomes, resulting in individualized therapeutic strategies as depicted in Figure 4.

Genetic variation affecting analgesic response is an important factor contributing to interindividual differences in pain treatment outcomes. Although various genetic determinants can impact therapeutic responses and adverse effects, polymorphisms in drug-metabolizing enzymes are arguably the most studied mechanism. Analgesics are often subject to extensive enzymatic biotransformation, and genetic variants affecting these pathways may result in altered enzyme activity that affects drug exposure, therapeutic efficacy and the likelihood of adverse effects. Nonetheless, the clinical consequences of individual variants are highly context-dependent and depend on disease, treatment strategy, and patient characteristics. As an example, the CYP2D6*2 polymorphism was not associated with analgesic response in PHN patients treated with tramadol; thus, its predictive value may be limited to certain clinical contexts [109]. Besides affecting metabolic enzymes, variant alleles of drug transporters might affect pharmacological responses by changing the distribution and availability of drugs. The ABCB1 rs1045642 polymorphism has been associated with differential analgesic responses to a combined treatment of nortriptyline and morphine, with certain genotypes showing greater therapeutic benefit [110]. These results suggest that while drug metabolism and transport pathways differ due to genetic variation, their clinical application remains limited and requires further validation.

Single-nucleotide polymorphisms (SNPs) related to nociceptive signalling pathways and potential therapeutic targets may also modulate response to analgesic treatment. SNPs in genes involved in pain transmission and opioid signalling pathways may influence sensitivity to various opioid-based therapies. Such genetic variability may, in part, account for differences between patients with chronic low back pain (CLBP), such as greater analgesic benefit in some patients and limited responses in others despite similar treatment strategies [111]. These findings lend support to potential clinical utility of incorporating genetic information in chronic pain management. In addition, variations in candidate genes may contribute to the response and adverse effects of cannabinoid-based treatments, thus directly or indirectly affecting efficacy and tolerability, including future treatment discontinuation [112].

In addition to pharmacological effects, genetic variations drive differences in intrinsic pain processing, such as individual pain sensitivity and susceptibility to chronic pain states. It is likely that genes affecting neurotransmitter regulation and pathways important in nociceptive signalling neural circuits modulate pain thresholds and contribute to the development of chronic pain phenotypes. Differentially expressed genes (DEGs) identified in patients with low back pain were found to be enriched in neuroinflammation-associated pathways, and key candidate genes KLRK1, LRRK2, NLRP3 and PLG were identified through LASSO regression and support vector machine (SVM) analyses [113]. In summary, genetic influences impact multiple aspects of neuropathic and chronic pain, including drug metabolism, treatment response, as well as the biological basis of pain susceptibility. This suggests that pharmacogenomic research, which is currently ongoing, may ultimately be incorporated into clinical decision-making to improve drug selection and optimize dosing strategies for more individualized analgesic therapy approaches.

5.2 Clinical implementation of personalized therapy

Precision dosing strategies have gained increasing utility in the individualization of NP management. Intrathecal drug delivery (ITDD) systems offer the potential for effective and localized administration of analgesic agents in chronic pain patients, particularly those with refractory NP. Clinical evidence has shown that ITDD pumps can maintain accurate dosing and consistent delivery performance when used with off-label medications or mixtures of drugs infused under different conditions [114]. The stability generated can help individualize treatment regimens according to pain severity, medication tolerance and therapeutic response for improving pain management. By increasing availability of the drug at the site of action and limiting systemic exposure with concomitant adverse effects, intrathecal delivery represents a therapeutic option for precision analgesia, thus offering an attractive approach compared with systemic administration.

Contemporaneously with drug delivery advances, digital health technologies are offering new opportunities for tailored treatment decision-making. Tools like the systematic individualized benefit–risk evaluation tool (SIBRET) can help clinicians and patients systematically weigh the potential benefits and risks of different therapeutic options, thereby supporting more informed treatment decisions [115]. Moreover, SIBRET has provided proof-of-concept evidence for the analgesic efficacy of topical 10% phenytoin cream, further illustrating the potential role of local treatment strategies in precision pain management [115]. Integrating patient characteristics, clinical outcomes, and risk assessments into modeling platforms may lead to more rational selection and optimization of therapeutic interventions.

Novel neuromodulation modalities also broaden the arsenal of personalized treatment options for NP. The closed-loop spinal cord stimulation (CL-SCS) systems employing ECAP feedback can provide continuous monitoring of neural responses and dynamic adjustment of stimulation parameters, further stabilizing neural activation [116]. ECAP-modulated CL-SCS provides enhanced neuromodulation control in cervical and thoracic spinal applications. Compared with wider-targeted neuromodulation, the design may improve analgesic efficacy, while reducing stimulation levels that are greater or lower than optimal and enhancing control of cervical neural structures with a narrow therapeutic window.

Altogether, precision drug delivery, digital decision-support systems and closed-loop neuromodulation indicate a move toward more individualized and data-informed NP management. At the same time, these systems are still in clinical development and much additional research will need to be done to delineate their mechanisms, optimize their integration with current treatments, and construct robust predictive paradigms. Table 2 highlights the key differences in mechanisms of action, delivery approaches and clinical applications between these personalized therapeutic modalities.

5.3 Future directions in personalized therapy

The trend of NP management is gradually changing from traditional empirical drug selection to more mechanism-informed and personalized therapy with the continued advancement of precision medicine. Multi-omics approaches in conjunction with other clinical characteristics lay an invaluable foundation for this transition. Integration of genomic, transcriptomic, proteomic and metabolomic analyses has advanced our understanding of the molecular networks involved in both initiation and maintenance of the pain state; this has enabled identification of targets for potential therapeutic intervention. Among these molecular properties, functional gene expression profiles in nociceptive neurons have gained increasing attention, especially ion channel-related genes including SCN9A, SCN10A, TRPV1, and TRPA1 that govern neuronal excitability and mediate calcium-dependent responses to external stimuli (such as capsaicin) [140]. Neuron-derived S100A4 has also been shown to modulate neurotoxic astrocyte reactivity and is associated with neuroinflammation and persistent pain, suggesting that S100A4 may represent a potential therapeutic target for NP [141]. Thus, the integration of multi-omics datasets with bioinformatic analyses to define molecular subtypes could allow for biologically based patient stratification and precision therapy.

A more detailed understanding of neuroimmune mechanisms has further broadened the possibilities for personalized NP treatment. Chronic pain involves inflammatory alterations within the central nervous system accompanied by neurophysiological changes, which are associated with distinct clinical pain phenotypes, particularly the severity of nociplastic pain [142]. Systematic characterisation of neuroimmune signalling networks may open up a path to elucidate biological heterogeneity in patients and identify novel therapeutic targets for mechanism-based intervention. Molecularly, regulation of TGFβ1 and GP130 signalling pathways has been suggested to participate in pain modulation in preclinical studies, positioning these targets as potential candidates for further translational research.

Beyond molecular classification, directed modulation of specific nociceptive pathways is emerging as a novel strategy in NP personalized therapy. Ion channel disorders, neuroimmune interactions and inflammatory signalling are not independent phenomena but interconnected regulatory networks that together promote the onset and maintenance of NP. Post-translational modifications of NaV1.7 can influence neuronal excitability, P2X3 receptor signalling interacts with microglial activation, and NLRP3 inflammasome activity contributes to pain maintenance [143-145]. In the meantime, however, alternative therapeutic strategies are being investigated. Sustained analgesic activity, improved glycaemic control and reduced opioid consumption are observed with inhaled cannabis in patients with refractory diabetic neuropathy while maintaining an acceptable safety profile. Future studies integrating biomarkers, such as levels of endogenous cannabinoids, may further elucidate the mechanisms underlying this therapeutic effect and refine patient selection for treatment response [146]. In general, the field of NP management is converging on a molecularly informed classification, mechanism-based intervention, and data-driven treatment decisions. There are still major hurdles to overcome, yet bringing together biological signatures, clinical phenotypes and insights into mechanisms is likely to move the field closer to precision therapy.

While mechanism-based research has greatly advanced our understanding of NP pathophysiology, translation of promising molecular findings into successful analgesic treatments remains an ongoing challenge. While many targets involved in neuronal excitability, neuroinflammation and neuroimmune regulation have shown analgesic potential in preclinical studies, only a small number of these targets have demonstrated effective clinical translation. This discrepancy between experimental success and clinical application mirrors the heterogeneity of human NP, which is a group of heterogeneous conditions rather than a single disease process. The differences in disease origin, lesion location, sensory phenotypes, molecular changes and personalized treatment responses still make it difficult to develop mechanism-guided therapies [1, 147]. Voltage-gated sodium channel Nav1.7 provides a representative example of the clinical challenges associated with translating genetically validated targets into analgesic therapies. Nav1.7 functions as a regulator of peripheral nociceptive signalling. Strong evidence supporting Nav1.7 as a potential analgesic target has been provided by human genetic studies, showing that gain-of-function mutations in SCN9A can cause inherited pain disorders including primary erythromelalgia and paroxysmal extreme pain disorder in humans, while loss-of-function mutations lead to congenital insensitivity to pain. These results stimulated the exploration of selective Nav1.7 inhibitors as potential therapeutic agents [1, 148]. Despite strong genetic support and promising data from experimental models, multiple Nav1.7 inhibitors have failed to achieve sufficient clinical efficacy. Possible explanations include incomplete target engagement in human tissues, compensatory effects of other sodium channel subtypes, discrepancies between preclinical models and human pain conditions, and the lack of robust biomarkers to identify patients whose pain will respond best. The Nav1.7 experience shows that successful translation requires a biologically attractive target, appropriate patient selection, adequate exposure to the drug tested and clinically meaningful outcome measures.

Similar translational challenges have been encountered with other mechanism-based targets. Nerve growth factor (NGF) signalling represents an attractive therapeutic target because NGF contributes to nociceptor sensitization, inflammatory responses, and pain amplification. Anti-NGF therapies have demonstrated substantial analgesic effects in preclinical studies and clinical trials of osteoarthritis-related pain; however, concerns regarding rapidly progressive osteoarthritis and joint safety have restricted their broader clinical application [149, 150]. These observations underscore that targeting a biologically relevant pathway alone does not necessarily ensure an adequate therapeutic window. Several factors contribute to the limited translation of mechanism-based analgesics. Current animal models have greatly contributed to the understanding of NP mechanisms; however, they mainly capture specific components of pain-related behaviors, such as stimulus-evoked hypersensitivity, and may not fully reproduce complex human pain experiences, including ongoing spontaneous pain, affective dimensions, and disease heterogeneity. Therefore, improving the clinical relevance of behavioral assessments remains an important challenge for translational pain research [151, 152]. Many candidate targets are involved in physiological neuronal functions, creating difficulties in achieving sufficient analgesia while preserving normal sensory processing. The absence of clinically validated biomarkers limits patient stratification and may obscure therapeutic benefits in biologically defined responder populations [147, 153].

Therefore, future development of mechanism-based therapies should move beyond traditional target-centric approaches toward integrated precision strategies. Combining human-relevant disease models, multi-omics profiling, molecular biomarkers, and clinical phenotyping may facilitate identification of mechanistically distinct NP subgroups. In addition, rational multi-target interventions that simultaneously regulate neuronal excitability, neuroinflammation, and immune–synaptic interactions may provide a more effective approach than single-target inhibition. Such strategies may improve the likelihood of successful translation from experimental discoveries to individualized NP treatment [1].

7.1 Integration of non-pharmacological interventions

In the comprehensive management of NP, pharmacotherapy alone is often insufficient to achieve sustained long-term efficacy, and non-pharmacological interventions are increasingly recognized as important adjunctive strategies. Approaches such as physical and exercise-based therapies, acupuncture and electroacupuncture, as well as neuromodulation techniques exert multi-level effects ranging from peripheral repair to central regulation. When combined with pharmacological treatment, these modalities provide complementary benefits and support a more integrated management framework.

Among physical and exercise-based interventions, photobiomodulation therapy (PBMT) and functional exercise demonstrate notable analgesic and rehabilitative potential. PBMT improves mitochondrial function, modulates inflammatory responses, and promotes neural regeneration through light stimulation at specific wavelengths, thereby reducing pain sensitivity. In parallel, aerobic exercise (for example, swimming) alleviates pain by regulating neuroimmune responses, and neural plasticity while preserving muscle function [154]. These findings support the value of multimodal non-pharmacological strategies in NP management.

Increasing evidence has elucidated the molecular and circuit-level mechanisms underlying acupuncture and electroacupuncture-mediated analgesia. Electroacupuncture modulates multiple stress-response and neuroprotective signalling pathways through stimulation of specific acupoints. For instance, it has been shown to inhibit ferroptosis via regulation of the SAT1/ALOX15 pathway, thereby alleviating NP and suggesting ferroptosis as a potential therapeutic target [155]. At acupoints such as Zusanli (ST36) and Baihui (GV20), electroacupuncture-induced analgesia may be associated with suppression of ferroptosis in spinal neurons, partially mediated by activation of the Nrf2 signalling pathway [156]. At the central level, electroacupuncture also modulates functional activity in pain-related brain regions. It has been reported to restore suppressed Tet1 expression in hippocampal neural stem cells (NSCs) and promote adult neurogenesis in the ventral dentate gyrus by alleviating Prox1 hypermethylation, thereby contributing to the long-term antidepressant effects of electroacupuncture in chronic neuropathic pain [157]. In addition, electroacupuncture attenuates NP by inhibiting endoplasmic reticulum stress mediated by BIP and IRE-1α in the anterior cingulate cortex, highlighting the role of ER stress in pain pathophysiology [158]. Clinically, electroacupuncture has been shown to alleviate multiple NP symptoms, including burning pain, electric shock–like sensations, and mechanical allodynia, while improving psychosocial function and quality of life; however, larger-scale studies are still required to validate its efficacy and generalizability [159].

Electroacupuncture treatment has been shown to provide neuromodulatory effects, and recent advances in neuromodulation have led to increasing attention toward the combination of electroacupuncture with other neuromodulation modalities. Electroacupuncture produces significant antinociceptive effects in models of chronic sciatic nerve compression that are increased by combined stimulation of the infralimbic region of the medial prefrontal cortex (mPFC), suggesting that different neuromodulatory strategies may have synergistic effects [160].

In conclusion, physical and exercise-based treatments, acupuncture and electroacupuncture, and neuromodulation strategies all exert analgesic effects through coordinated regulation of inflammatory responses, cellular stress pathways, and central neural networks. Integration of these non-pharmacological strategies with pharmacotherapy may facilitate a more holistic and individualized treatment paradigm, which could improve pain control as well as affective and behavioural changes associated with chronic pain while also paving the way for integration with psychological and behavioural therapies.

7.2 Synergistic effects of psychological and behavioural interventions

In the comprehensive management of NP, pharmacological treatment alone is often insufficient to achieve satisfactory symptom control, and the incorporation of non-pharmacological strategies has become an important component of multimodal care. Evidence indicates that, among patients with comorbid anxiety and depression, pharmacological therapies, including antiepileptic and antidepressant agents, remain fundamental treatment options, whereas early integration of non-pharmacological interventions focused on physical activity may provide additional benefits in pain management and recovery from pain-related disability [161]. Accordingly, behavioural interventions and lifestyle-oriented strategies have become important components of multidisciplinary pain management. Patients with NP frequently experience emotional distress, impaired sleep, and reduced physical activity, which may further reinforce pain persistence through complex neuropsychological mechanisms. Structured behavioural approaches, including cognitive–behavioural therapy, graded activity programmes, and pain coping skills training, aim to modify maladaptive pain-related perceptions, reduce catastrophizing, and improve emotional regulation and coping capacity.

Lifestyle interventions also play a meaningful role in the long-term management of chronic pain. Exercise, sleep hygiene, and psychological techniques may modulate pain processing through multiple biological and psychological pathways. Aerobic exercise has been shown to enhance neural plasticity and increase the amplitude of transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs), suggesting its involvement in regulating cortical excitability and supporting functional recovery. There is a strong association between sleep disruption and greater pain interference, whereas the relationship between sleep quality and pain severity seems to be bidirectional [162, 163]. Moreover, mindfulness-based interventions have been shown to decrease pain intensity and unpleasantness as well as reduce negative emotional responses to pain [164]. Collectively, these findings indicate that exercise, sleep regulation, and psychological interventions may influence both neural and subjective pain processing and serve as effective adjuncts to NP management.

The rapid development of digital health technologies for behavioural support and self-management of chronic pain has provided additional opportunities as well. Psycho-educational interventions based on combined disease-specific information and multidisciplinary self-management strategies, such as those developed for endometriosis, have been shown to reduce symptom burden, anxiety, depression and NP while improving disease-related knowledge and quality of life [165]. Digital interventions such as mobile applications, web-based learning platforms and remote monitoring systems enable ongoing delivery of pain education, psychosocial support and symptom monitoring, facilitating enhanced patient engagement and tailored management. Combining behavioural therapy, lifestyle modification, and digital interventions may provide additional benefits for long-term outcomes. Such approaches are characterized by a multidisciplinary practice involving medical, psychological and rehabilitation perspectives; thus, their application requires effective collaboration among various health professionals. Patient-centred, team-based care models may ultimately offer a more integrated framework for optimizing NP management while facilitating the delivery of improved and personalized treatment strategies.

7.3 Role of multidisciplinary teams (MDTs) in pain management

The management of NP is inherently multifaceted, and one-discipline-based approaches are often insufficient due to the diverse clinical manifestations and long-term care needs. MDTs offer a more integrated structure by bringing together the expertise of specialists, which fosters comprehensive assessment, collaborative clinical decision-making and personalized treatment approaches. MDTs may enhance the quality of both therapeutic decision-making and the delivery of care for pain through this collaborative model.

Clinical pharmacists within multidisciplinary pain management programmes have become more involved in optimizing pharmacological treatment. Clinical pharmacists involved in interdisciplinary care models have been shown to significantly reduce the overall medication use over five or more follow-up visits for patients undergoing chronic opioid therapy (COT). In addition, pharmacist-led interventions can improve adherence to guideline-recommended prescribing practices, optimize prescriptions with and without an opioid component, and increase access to evidence-based care [166]. Likewise, current guidelines for trigeminal neuralgia (TN) indicate MDT-based methods for both acute and chronic management. These approaches place a greater emphasis on collaborative evaluation and evidence-based decision-making, and treatments can be adapted according to ongoing assessments of clinical outcomes [167].

MDT-based care helps maximize pharmacotherapy, but also has potential benefits for longer-term outcomes in people with chronic pain. Psychological factors are closely associated with changes in pain-related disability, and early assessment of the psychological domain may facilitate earlier and more individualized multidisciplinary interventions [168]. In clinical contexts, MDT approaches combine pharmacologic, psychological, and rehabilitative strategies to deliver integrated pain management. Patients receiving MDT interventions have shown better pain control and improvement in functional outcomes at follow-up compared with conventional care, including a significant reduction in movement-related pain scores at 3 months [169].

In summary, structured multidisciplinary collaboration is an important part of modern NP management. MDTs offer more patient-centered individualized care through a multidisciplinary approach, with expertise spanning clinical, psychological, and rehabilitation domains. This model provides an important approach toward advancing more personalized pain management and improving treatment outcomes, although it may vary in its implementation within healthcare settings.

Recent evidence indicates that NP may be better understood as a complex pathological condition arising from dysregulation of neuro–immune–synaptic networks rather than simply as a consequence of peripheral nerve injury. Following nerve injury, microglia and astrocytes undergo rapid activation, releasing pro-inflammatory mediators while concurrently promoting synaptic plasticity and increasing the excitability of dorsal horn neurons. Enhanced neuronal activity further reinforces neuroinflammatory signalling, resulting in the establishment of a sustained neuroimmune positive feedback loop. Within this regulatory framework, the Hv1 proton channel has emerged as an important modulatory component. Hv1 contributes to reactive oxygen species (ROS) generation in microglia following spinal nerve transection (SNT), facilitates astrocyte activation, and increases interferon-γ (IFN-γ) expression, ultimately promoting pain hypersensitivity [170]. These findings highlight the potential of targeting neuroimmune interactions and ion channel-mediated signalling pathways as therapeutic strategies for NP.

Despite the availability of multiple pharmacological interventions, the overall therapeutic efficacy of current treatments remains suboptimal. Existing analgesic approaches primarily focus on modulating neurotransmitter systems or reducing neuronal hyperexcitability. For example, the tricyclic antidepressant amitriptyline produces analgesic effects through inhibition of serotonin and noradrenaline reuptake; although approved by the US Food and Drug Administration (FDA) for depression treatment, it is widely used in clinical practice for NP management [171]. Similarly, calcium channel modulators, including gabapentin and pregabalin, are regarded as first-line treatments, with gabapentin demonstrating a favourable balance between analgesic efficacy and tolerability, thereby supporting long-term treatment adherence [172]. Meanwhile, novel ion channel-targeting agents continue to be explored. The voltage-gated sodium channel modulator vixotrigine has demonstrated good tolerability at single doses of up to 825 mg and repeated administration of 450 mg twice daily [173]. In addition, transient receptor potential (TRP) channels are important regulators of peripheral inflammatory pain. Increased TRPV1 expression and reduced TRPM8 activity contribute to enhanced nociceptive signalling, whereas TRPM8 activation can suppress TRPV1 function in DRG neurons, providing a potential mechanism underlying the analgesic effects of menthol [174]. Collectively, these findings suggest that although modulation of specific molecular pathways can provide partial relief in NP, the complex interactions among neuroinflammation, synaptic plasticity, and neural repair processes limit the efficacy of single-target interventions. Therefore, therapeutic strategies capable of simultaneously addressing multiple pathological mechanisms may better reflect the biological complexity of NP.

With the advancement of precision medicine, therapeutic strategies for NP are gradually transitioning from empirical treatment toward individualized approaches. Nevertheless, personalized NP management remains at an early stage, largely owing to the limited availability of reliable predictive biomarkers and validated decision-making frameworks. Future studies should focus on integrating multi-omics datasets, clinical phenotypes, and real-world evidence to establish comprehensive patient stratification systems that can facilitate treatment optimization. Furthermore, integrated therapeutic approaches combining multi-target pharmacological interventions, neuroimmune modulation, and regenerative strategies may offer a more effective framework for precision analgesia. The shift from single-mechanism therapies toward network- and system-level regulation will be essential for developing mechanism-based and personalized treatment strategies for NP.

As a narrative review rather than a systematic review or meta-analysis, this study may be subject to potential selection and interpretation bias, and quantitative estimates of therapeutic efficacy were not performed. Although systematic reviews and meta-analyses have generated important evidence regarding pharmacological interventions for NP, substantial heterogeneity remains across studies, including differences in disease etiology, diagnostic criteria, treatment duration, and outcome measurements, which limits direct comparisons among therapeutic strategies [1, 27]. The evidence summarized in this Review spans multiple stages of therapeutic development, from cellular and animal experiments to early clinical investigations and established treatment approaches. These distinct levels of evidence should be interpreted according to their respective translational contexts rather than being considered directly comparable.

Importantly, many mechanism-based targets that demonstrate efficacy in experimental models have failed to achieve successful clinical translation, largely due to discrepancies between preclinical models and human NP conditions, insufficient target specificity, and the absence of reliable biomarkers for identifying responsive patient populations [151, 175]. Several emerging therapeutic strategies, including stem cell-based therapies, exosome-derived products, nanomedicine, pharmacogenomics-guided interventions, and closed-loop neuromodulation, are currently being actively explored. Although these approaches have demonstrated encouraging biological effects in preclinical models and early-stage clinical studies, their widespread clinical implementation will require further evidence regarding long-term efficacy, safety profiles, manufacturing consistency, and cost-effectiveness. Nanomedicine, in particular, has shown considerable potential for improving drug targeting and enhancing therapeutic bioavailability. However, challenges associated with in vivo distribution, large-scale manufacturing, regulatory approval, and long-term safety evaluation remain major barriers limiting clinical translation [107, 108]. Similarly, pharmacogenomic strategies designed to guide analgesic selection require additional prospective clinical validation before they can be routinely integrated into NP management [176]. NP represents a biologically diverse group of disorders caused by multiple etiologies, including peripheral nerve injury, diabetes, chemotherapy, infection, and SCI. The considerable variation in clinical manifestations, underlying molecular mechanisms, and treatment responsiveness suggests that mechanism-based therapies are unlikely to provide consistent benefits across all patients without reliable approaches for patient stratification [153]. Future studies combining detailed clinical phenotyping, molecular biomarker identification, multi-omics profiling, and prospective clinical validation will be critical for refining patient classification and advancing more individualized therapeutic strategies for NP.

NP is a biologically heterogeneous condition, arising from complex interactions among neuronal hyperexcitability, neuroimmune activation, glial dysfunction, synaptic plasticity and pain-processing network remodeling. While conventional pharmacological therapies still constitute the core of clinical management, their suboptimal efficacy and the unwanted side effects associated with treatment indicate a necessity for therapeutic approaches more closely tailored to the underlying disease processes. In this Review, we assess recent advances in pharmacological therapies and novel approaches to alleviate NP within a mechanism-to-translation framework. Instead of focusing on experimental effectiveness alone in appraising potential therapies, we use a broader framework that integrates biological plausibility, strength of evidence, clinical feasibility, and translational limitations. This viewpoint highlights that for the successful development of NP treatments, not only do promising molecular targets need to be discovered but responsive patient populations need to be precisely defined and predictive biomarkers need to be established, which requires a more concerted effort.

Although there has been great progress in understanding NP pathophysiology, translating mechanism-based discoveries into effective clinical therapies remains challenging. Numerous promising targets identified in preclinical studies have failed to translate into substantial clinical benefit, which likely highlights issues in disease modeling, target selectivity, and the significant inter-patient NP heterogeneity. Novel strategies such as stem cell therapies, nanomedicine approaches, pharmacogenomics-guided methods and closed-loop neuromodulation appear to offer exciting avenues for future therapy but need to be validated in well-designed studies prior to widespread clinical application. The future management of NP will likely depend on the combination of mechanistic classification, molecular biomarkers, multi-omic approaches and detailed clinical phenotyping in order to provide a better basis for precision medicine. Adopting approaches that target mechanisms involved in neuropathic pain rather than relying on empirically driven interventions for the management of clinical symptoms may lead to enhanced outcomes and reduce the substantial burden associated with chronic NP.

BLA, Basolateral amygdala; BPA, Bisphenol A; CLBP, Chronic low back pain; CL-SCS, Closed-loop spinal cord stimulation; CLU, Clusterin; COT, chronic opioid therapy; COX, Cyclooxygenase; DEGs, Differentially expressed genes; DRG, dorsal root ganglia; ECAP, Evoked compound action potential; eEF2K, Eukaryotic elongation factor 2 kinase; FDA, Food and Drug Administration; FDCs, Fixed-dose combinations; HUC-MSCs, Human umbilical cord–derived MSCs; IFN-γ, interferon-γ; ITDD, Intrathecal drug delivery; KYNA, Kynurenic acid; MDTs, Multidisciplinary teams; MEPs, Motor evoked potentials; mGluR5, metabotropic glutamate receptor 5; mPFC, Medial prefrontal cortex; MSCs, Mesenchymal stem cells; NGF, Nerve growth factor; NMDARs, NMDA receptors; NP, Neuropathic pain; NSAIDs, Nonsteroidal anti-inflammatory drugs; PAG, Periaqueductal grey; PBMT, Photobiomodulation therapy; PHN, Postherpetic neuralgia; PPARG, Peroxisome proliferator-activated receptor-γ; QA, Quinolinic acid; ROS, reactive oxygen species; SCI, Spinal cord injury; SNPs, Single-nucleotide polymorphisms; SNT, spinal nerve transection; STAT3, signal transducer and activator of transcription 3; SVM, Support vector machine; TMS, Transcranial magnetic stimulation; TN, trigeminal neuralgia; TRP, Transient receptor potential.

Author contributions

Rui Zhao conceived the review topic, performed the literature search and analysis, drafted and revised the manuscript, prepared the figures, and approved the final version of the manuscript.

Funding

This research received no external funding.

Data availability

Data sharing is not applicable to this article, as no new datasets were generated or analyzed during the current study. All information is derived from publicly available articles and datasets.

Ethics approval and consent to participate

Not applicable. This manuscript does not contain any studies involving human participants or animals performed by any of the authors.

Consent for publication

Not applicable. This manuscript does not include details, images, or videos relating to an individual person.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

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