Neuroinflammation and Oxidative Stress in Neuropathic Pain: Mechanistic Targets for Nutraceutical-Based Interventions

Abstract

Neuropathic pain is a chronic, difficult-to-treat condition arising from injury or disease of the somatosensory nervous system. Current pharmacological treatments provide limited relief for many patients and are often associated with adverse effects, highlighting the need for complementary mechanism-based strategies. Neuroinflammation and oxidative stress are pivotal and interdependent drivers of neuropathic pain, promoting glial activation, cytokine release, mitochondrial dysfunction, redox imbalance, ion channel sensitization, and peripheral and central sensitization. Nutraceuticals and dietary bioactive compounds have gained attention because of their pleiotropic actions, i.e., multiple pharmacological activities, on inflammatory, oxidative, metabolic, mitochondrial, and neuroimmune pathways. This review summarizes the mechanistic roles of neuroinflammation and oxidative stress in neuropathic pain and discusses evidence supporting nutraceutical-based interventions, including polyphenols, terpenoids, alkaloids, fatty acids and lipid-derived compounds, antioxidant nutraceuticals, vitamins, and micronutrients. Preclinical studies indicate that these compounds can attenuate pain-related behaviors by modulating redox-sensitive inflammatory signaling, glial reactivity, mitochondrial function, nociceptive ion channels, and endogenous antioxidant defenses. Although clinical evidence remains limited, selected compounds, including alpha-lipoic acid, palmitoylethanolamide, omega-3 fatty acids, B-complex vitamins, vitamin D, and capsaicin, show translational promise. Future studies should prioritize standardized formulations, bioavailability, dosing, safety, mechanistic biomarkers, and robust randomized trials to clarify their clinical role as complementary, multi-target strategies for neuropathic pain management.

1. Introduction

Neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system” [1,2]. Unlike nociceptive pain, which results from the activation of peripheral nociceptors by tissue injury or inflammation, neuropathic pain originates from pathological alterations within the peripheral or central nervous system and is characterized by maladaptive changes in neuronal signaling [3,4]. Clinically, neuropathic pain presents with a range of sensory abnormalities, including spontaneous pain, burning sensations, electric shock-like pain, paresthesia, dysesthesia, mechanical allodynia, and thermal or mechanical hyperalgesia [4,5]. These symptoms often persist long after the initial injury or disease has resolved and are frequently accompanied by significant emotional, cognitive, and functional impairments [6].

Neuropathic pain affects approximately 7–10% of the general population and represents a major public health challenge worldwide [7]. Neuropathic pain is prevalent among middle-aged and older adults with diverse underlying etiologies and is associated with a greater health burden than non-neuropathic pain [8]. It is associated with a broad spectrum of conditions, including diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia, traumatic nerve injuries, spinal cord injury, multiple sclerosis, and stroke [4,9]. The chronic nature of neuropathic pain imposes a substantial socioeconomic burden through increased healthcare utilization, reduced productivity, disability, sleep disturbances, anxiety, depression, and diminished quality of life [6,10]. Consequently, neuropathic pain remains one of the most debilitating and difficult-to-manage chronic pain conditions [4].

Current pharmacological management relies primarily on antidepressants, anticonvulsants, topical agents, and, in some cases, opioids [11,12]. However, therapeutic outcomes remain unsatisfactory for many patients. Available treatments often provide only partial pain relief, with less than half of treated individuals achieving clinically meaningful reductions in pain intensity [11,13]. Furthermore, dose-limiting adverse effects, poor tolerability, drug interactions, and concerns regarding long-term safety, particularly with opioid use, frequently compromise treatment adherence and effectiveness [11,13]. These limitations highlight the urgent need for novel therapeutic approaches capable of addressing the underlying biological mechanisms that sustain neuropathic pain.

The pathophysiology of neuropathic pain is highly complex and involves dynamic interactions between neurons, glial cells, immune cells, and multiple intracellular signaling pathways [14,15,16]. Peripheral nerve injury or disease initiates a cascade of molecular and cellular events that promote both peripheral and central sensitization [17]. Peripheral sensitization refers to the “increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields” [18,19], while central sensitization refers to the “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input” [19,20]. These processes include alterations in ion channel expression and function, aberrant neurotransmitter release, activation of immune and glial cells, and extensive neuroplastic changes within pain-processing pathways [14,17,21]. Rather than being driven by a single pathological mechanism, neuropathic pain emerges from the convergence of multiple interconnected processes that collectively contribute to its initiation, maintenance, and chronification. Among these mechanisms, neuroinflammation and oxidative stress have emerged as central contributors to neuropathic pain pathogenesis [14,16,22,23]. Following nerve injury, activation of resident and infiltrating immune cells, together with microglia, astrocytes, Schwann cells, and satellite glial cells (SGCs), leads to the sustained production of pro-inflammatory cytokines, chemokines, growth factors, and other inflammatory mediators [14,24,25]. These molecules enhance neuronal excitability and facilitate central sensitization [14,16]. Simultaneously, excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), often driven by mitochondrial dysfunction and activation of enzymatic oxidant systems, promotes cellular damage and further amplifies inflammatory signaling [22,26]. Importantly, neuroinflammation and oxidative stress are tightly interconnected processes that reinforce one another through reciprocal positive feedback loops involving key signaling pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and the NLRP3 inflammasome [23,27,28]. This bidirectional interaction contributes substantially to the persistence of neuropathic pain and represents an attractive target for therapeutic intervention [23,28].

In recent years, growing attention has been directed toward nutraceuticals and dietary bioactive compounds as complementary or alternative approaches for the management of chronic pain disorders [29,30,31,32]. Nutraceuticals encompass a diverse group of naturally occurring compounds derived from foods and food sources, including polyphenols, flavonoids, terpenoids, alkaloids, fatty acids, vitamins, minerals, and other bioactive molecules [30,33]. Unlike conventional pharmacological agents that often target a single molecular pathway, many nutraceuticals exert pleiotropic actions and can simultaneously modulate multiple biological processes involved in neuropathic pain [30,31]. Experimental and emerging clinical evidence suggests that these compounds may attenuate neuroinflammation, reduce oxidative stress, improve mitochondrial function, regulate glial activation, modulate nociceptive ion channels, and enhance endogenous antioxidant defenses [29,31,32,33]. Such multi-target properties make nutraceuticals particularly attractive candidates for mechanism-based interventions in complex disorders such as neuropathic pain.

Several previous reviews have discussed nutritional interventions for chronic pain, dietary supplements in neuropathic pain, phytochemicals, or bioactive compounds with analgesic potential. However, most have focused primarily on clinical efficacy, selected supplement categories, preclinical pharmacological effects, or broad nutritional approaches. In contrast, the present review specifically integrates the reciprocal mechanistic relationship between neuroinflammation and oxidative stress in neuropathic pain and links this crosstalk to nutraceutical-based interventions across multiple compound classes. Particular emphasis is placed on redox-sensitive inflammatory pathways, glial activation, mitochondrial dysfunction, inflammasome signaling, nociceptive ion channels, endogenous antioxidant defenses, and translational gaps.

Therefore, the aim of this review is to provide a comprehensive overview of the roles of neuroinflammation and oxidative stress in the development and maintenance of neuropathic pain and to discuss how these interconnected mechanisms may be targeted through nutraceutical interventions. Particular emphasis is placed on the molecular pathways underlying neuroimmune and redox dysregulation, as well as on the current evidence supporting the therapeutic potential of major classes of nutraceutical compounds. By integrating mechanistic insights with preclinical and clinical findings, this review seeks to evaluate the potential contribution of nutraceuticals as complementary and multi-target strategies for the management of neuropathic pain and to identify future directions for research and clinical translation.

2. Literature Search Strategy

This narrative review was based on a structured literature search of PubMed, Scopus, and Web of Science databases. The search covered references published from 1983 through 2026, corresponding to the publication years of the studies cited in this review. Searches were performed using combinations of the following terms: “neuropathic pain”, “neuroinflammation”, “oxidative stress”, “reactive oxygen species”, “mitochondrial dysfunction”, “nutraceuticals”, “dietary supplements”, “polyphenols”, “flavonoids”, “terpenoids”, “alkaloids”, “antioxidants”, “anti-inflammatory”, “vitamins”, and “micronutrients”. Preclinical studies, clinical trials, systematic reviews, meta-analyses, and mechanistic studies were considered when relevant to neuropathic pain mechanisms or nutraceutical interventions. Priority was given to studies addressing neuroinflammatory, oxidative, mitochondrial, glial, or nociceptive signaling pathways. Articles not directly related to neuropathic pain or lacking mechanistic or therapeutic relevance were excluded. Preference was also given to peer-reviewed studies providing mechanistic insights and/or evidence from well-established experimental models or clinical investigations. When multiple studies addressed similar mechanisms, representative and complementary publications were selected to provide a balanced overview of the available evidence. Because the objective of this work was to provide a comprehensive narrative synthesis of current knowledge rather than a systematic evidence synthesis, the review did not follow PRISMA guidelines and no formal risk-of-bias assessment was performed.

3. Neuroinflammation as a Key Driver of Neuropathic Pain

Neuroinflammation emerges as a primary driver of neuropathic pain following peripheral nerve injury or disease affecting the somatosensory system, arising from sustained activation of glial cells and intracellular inflammatory signaling cascades in the spinal cord and supraspinal regions, which ultimately promote neuronal hyperexcitability and pain chronification [34,35]. Unlike nociceptive pain, neuropathic pain is strongly associated with persistent neuroinflammatory processes that contribute to its initiation, maintenance, and progression [36]. These processes reflect tightly orchestrated yet ultimately maladaptive interactions between neurons, glial cells, and immune mediators across the peripheral and central nervous systems, where inflammatory signaling and oxidative stress reinforce each other in a self-perpetuating loop [37,38].

3.1. Immune Cells and Inflammatory Cascades Following Peripheral Nerve Injury

Following peripheral nerve injury, a complex inflammatory cascade is triggered. Damaged axons activate the extracellular signal-regulated MAPK pathway in Schwann cells, promoting immune cell recruitment and inflammatory mediator production [39]. Demyelination of injured peripheral nerves usually occurs through Wallerian degeneration, an inflammatory response that occurs after nerve injury, in which the distal portion of the axon degenerates after losing connection and trophic support from the neuronal cell body [40,41]. Resident immune cells, including mast cells, are rapidly activated and release histamine, serotonin (5-HT), prostaglandin E2 (PGE₂), bradykinin, nerve growth factor (NGF), and leukotrienes, which directly sensitize nociceptors and promote neutrophil recruitment [42,43,44]. Neutrophils infiltrate the damaged tissue during the early inflammatory phase and facilitate the activation and recruitment of macrophages and T lymphocytes [45,46]. Macrophages play a key role in phagocytosing myelin debris and injured axons, thereby contributing to Wallerian degeneration, while simultaneously releasing pro-inflammatory cytokines that amplify nociceptive signaling [47,48,49,50]. T cells further modulate the inflammatory milieu by releasing both pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17, and anti-inflammatory cytokines, including IL-4 and IL-10 [51,52]. Notably, regulatory T cells (Tregs) have been shown to exert anti-nociceptive effects by suppressing effector immune responses and promoting the resolution of neuroinflammation. Furthermore, their depletion exacerbates neuropathic pain behaviors in preclinical models [51]. In parallel, sensory nerve terminals release vasoactive neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) peripherally, increasing vascular permeability and enhancing immune cell infiltration at the site of injury through a mechanism known as neurogenic inflammation [53,54]. Within days after injury, immune cell infiltration into the dorsal root ganglion (DRG) promotes cytokine-mediated sensitization of primary sensory neurons [4,24,55,56,57]. Moreover, colony-stimulating factor 1 (CSF-1) released from injured afferents activates spinal microglia and astrocytes, leading to further production of neuroinflammatory mediators within the dorsal horn [4,47,55]. These mediators enhance excitatory synaptic transmission and may induce apoptosis of inhibitory GABAergic interneurons, thereby reducing spinal inhibitory control and facilitating central sensitization [4].

3.2. Pro-Inflammatory Cytokines in Neuropathic Pain Hypersensitivity

Pro-inflammatory cytokines are central mediators of neuropathic pain hypersensitivity. IL-1β enhances excitatory currents, reduces inhibitory synaptic transmission, and sensitizes nociceptors through direct activation of transient receptor potential vanilloid type 1 (TRPV1) channels and increased prostaglandin synthesis [58,59,60,61]. TNF-α acts as a potential initiator of neuropathic pain by sensitizing C-fibers and DRG neurons, and its signaling is closely associated with mechanical allodynia, a painful response to a stimulus that is normally non-noxious, and hyperalgesia, an exaggerated pain response to a noxious stimulus [62,63,64]. IL-6 has also been implicated in thermal hyperalgesia and mechanical hypersensitivity [65]. These cytokines activate intracellular signaling pathways such as MAPK, including p38 and c-Jun N-terminal kinase (JNK), and NF-κB, which regulate transcription of additional inflammatory mediators and modulate ion channel expression [61,66].

Inflammatory mediators directly alter ion channel function in nociceptors, lowering activation thresholds and increasing neuronal excitability. Histamine, prostaglandins, bradykinin, NGF, and substance P can directly activate or sensitize sensory terminals [41,67,68]. NGF, in particular, enhances thermal and mechanical hyperalgesia through modulation of TRPV1 and sodium channels [67,68]. Collectively, these molecular changes promote peripheral sensitization and facilitate synaptic transmission in the spinal dorsal horn, contributing to the development of persistent allodynia and hyperalgesia, both hallmarks of neuropathic pain.

3.3. Glial Cells as Orchestrators of Neuroinflammation

Microglia are the innate immune cells of the central nervous system, functioning as vigilant sentinels that quickly detect danger-associated molecular patterns (DAMP) released following nerve injury. In response, they proliferate, undergo morphological and functional changes, associated with a predominantly pro-inflammatory activation state, particularly within the dorsal horn of the spinal cord [69,70,71]. Activated microglia upregulate purinergic (e.g., P2X4, P2X7), chemokine, and Toll-like receptors (TLRs), leading to the production of TNF-α, IL-1β, IL-6, brain-derived neurotrophic factor (BDNF), and prostaglandins, which enhance synaptic transmission by increasing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartate (NMDA) receptor conductance and reduce inhibitory GABAergic tone, thereby contributing to mechanical allodynia and thermal hyperalgesia [27,71,72,73,74,75]. In the peripheral nervous system, however, microglia are absent; their functional role in the DRG is instead fulfilled by resident macrophages and SGCs, forming a macrophage-SGC-neuron triad in response to signals of nerve injury. This macrophage–SGC–neuron triad communicates through adenosine triphosphate (ATP) and other inflammatory mediators, contributing to the initiation, maintenance, and progression of inflammation-associated neuropathic pain [76]. In addition, following peripheral nerve injury, Schwann cells contribute to Wallerian degeneration by degrading myelin and releasing inflammatory signals [40].

Astrocytes, which normally maintain ion homeostasis, neurotransmitter uptake, and blood–brain barrier integrity, also undergo reactive astrogliosis following peripheral or central nerve injury, characterized by upregulation of glial fibrillary acidic protein (GFAP), hypertrophy of processes, and altered expression of connexins and transporters. Reactive astrocytes sustain and amplify neuroinflammation by releasing cytokines (TNF-α, IL-1β), chemokines (CCL2, CXCL1, CXCL12), ATP, and glutamate through hemichannels such as connexin 43 (Cx43), which activate microglia and neurons, and facilitate long-term maintenance of neuropathic pain states [77,78,79,80].

Beyond their individual contributions, microglia and astrocytes engage in a tightly regulated bidirectional signaling network that sustains chronic neuroinflammation. Following nerve injury, activated microglia release pro-inflammatory mediators such as TNF-α and IL-1β, which induce reactive astrogliosis and enhance the activity of astrocytic Cx43 and pannexin-1 (Panx1) hemichannels. Increased hemichannel opening promotes the extracellular release of ATP and glutamate, thereby amplifying neuron–glia communication [78,80,81,82]. Extracellular ATP activates purinergic receptors, particularly P2X7 receptors expressed by microglia [83,84], leading to further release of TNF-α, IL-1β, and other inflammatory mediators, as well as NLRP3 inflammasome activation and ROS production [83,84]. Concurrently, astrocyte-derived glutamate enhances excitatory neurotransmission and reduces inhibitory control within dorsal horn circuits, contributing to central sensitization [77,80]. Consequently, a self-perpetuating microglia–astrocyte amplification loop is established, representing a critical upstream mechanism linking neuroinflammation, oxidative stress, and persistent neuropathic pain [71,81]. Importantly, several nutraceuticals discussed in this review may interfere with components of this pathway through their ability to suppress glial activation, inhibit NF-κB/MAPK/NLRP3 signaling, reduce oxidative stress, and modulate purinergic and glutamatergic signaling [77,81].

Continuous bidirectional communication between microglia and astrocytes, mediated by soluble factors and type I interferon (IFN-I) signaling, establishes a self-sustaining inflammatory cycle. Experimental studies have shown that selective modulation or depletion of either astrocytes or microglia can reduce neuropathic pain [80,81,85,86]. Importantly, microglial pyroptosis, a highly inflammatory form of programmed cell death mediated by gasdermin D following caspase-1 activation, may have a dual role. Although it can locally enhance inflammation, it may also help limit neuroinflammation by removing excessively activated microglial cells. This complex effect should be considered when developing therapeutic strategies targeting glial cell activation.

3.4. Pro-Inflammatory Signaling Pathways: NF-κB, MAPKs, and the NLRP3 Inflammasome

A central node in glial-driven neuroinflammation is NF-κB, which is activated in microglia and astrocytes by pro-inflammatory cytokines, pattern-recognition receptor signaling, and oxidative stress, leading to nuclear translocation of p65 subunits and transcription of genes encoding TNF-α, IL-1β, IL-6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS). In neuropathic pain models, including chronic constriction injury (CCI) and spinal nerve ligation, pharmacological or genetic inhibition of NF-κB in the spinal cord reduces inflammatory mediator expression and alleviates mechanical allodynia, highlighting this pathway as a key mechanistic target [61,66].

MAPKs, including p38 MAPK, extracellular signal-regulated kinase (ERK), and JNK, are also activated in microglia and astrocytes following nerve injury. These kinases integrate upstream signals from cytokines, chemokines, and ROS, regulating both transcriptional and post-translational mechanisms involved in pain sensitization [87]. In CCI and spared nerve injury models, activation of p38 MAPK in spinal microglia correlates temporally with the onset of mechanical allodynia and thermal hyperalgesia, whereas intrathecal administration of p38 or ERK inhibitors reduces the production of TNF-α, IL-1β, and BDNF, thereby attenuating central sensitization and spontaneous pain behaviors [61,66].

Another pivotal signaling platform in neuropathic pain is the NLRP3 inflammasome, which functions as a sensor of mitochondrial dysfunction, oxidative stress, and ionic disturbances in microglia and, to a lesser extent, astrocytes [59]. Although NLRP3 inflammasome signaling has traditionally been associated with glial cells and other immune cells, growing evidence indicates that primary sensory neurons also express functional inflammasome components [88,89]. In sensory neurons, mitochondrial dysfunction, oxidative stress, metabolic stress, and disturbances in ionic homeostasis may promote NLRP3 activation, indicating that inflammasome signaling contributes not only to neuroimmune responses but also to neuronal dysfunction during neuropathic pain. Activation of the NLRP3 inflammasome occurs through two mechanistically distinct steps. An initial priming phase is triggered by inflammatory mediators and pattern-recognition receptor signaling, resulting in NF-κB-dependent transcriptional upregulation of NLRP3, pro-IL-1β, and pro-IL-18 [88,90,91]. A subsequent activation phase is induced by danger-associated signals, including extracellular ATP, ROS accumulation, mitochondrial dysfunction, lysosomal disruption, and ionic fluxes, promoting NLRP3 oligomerization, recruitment of the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1 activation (NLRP3/ASC/Caspase-1 axis), leading to maturation of IL-1β and IL-18 [90,91,92]. Inflammasome activation may also trigger gasdermin D-mediated pyroptosis, thereby amplifying local inflammatory responses and promoting central sensitization and mechanical allodynia. Beyond cytokine maturation, neuronal NLRP3 activation has been implicated in axonal degeneration, neuronal dysfunction, and increased nociceptor excitability, suggesting a direct contribution to neuropathic pain initiation. Moreover, neuronal inflammasome activation may further amplify glial inflammatory responses, reinforcing the bidirectional crosstalk between stressed neurons and activated glial cells that underlies neuroimmune dysregulation in neuropathic pain [88,89]. This distinction between priming and activation is mechanistically important because therapeutic interventions may selectively target one or both phases of inflammasome signaling.

Importantly, neuroinflammation and oxidative stress are tightly interconnected processes that mutually reinforce neuropathic pain. Sustained production of ROS and RNS in injured sensory neurons and spinal cord microglia not only damages cellular macromolecules but also acts as a signaling mechanism [93]. ROS activate redox-sensitive pathways, including NF-κB and MAPKs, promoting the expression of pro-inflammatory cytokines and iNOS [94,95]. In turn, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-derived and mitochondrial-derived ROS facilitate both NF-κB-dependent inflammasome priming and NLRP3 activation, leading to caspase-1 activation, IL-1β/IL-18 maturation, and, in some models, pyroptotic cell death, all of which contribute to central sensitization and mechanical allodynia [88]. Conversely, activation of NF-κB and the NLRP3 inflammasome further enhances ROS production through NOX2 activation and mitochondrial dysfunction, establishing a self-perpetuating feed-forward loop between oxidative stress and neuroinflammation that sustains neuropathic pain [38].

This mechanistic framework is particularly relevant for nutraceutical interventions because different bioactive compounds appear to interfere with distinct stages of the inflammatory cascade. Several nutraceuticals reviewed herein suppress NF-κB signaling and therefore are likely to predominantly inhibit the priming phase of NLRP3 inflammasome activation [96,97,98,99]. In contrast, others reduce mitochondrial ROS production, improve mitochondrial function, and/or attenuate purinergic signaling, thereby limiting inflammasome activation and downstream neuroinflammatory responses [100,101,102,103,104,105,106,107,108,109,110,111]. Because several nutraceuticals possess both antioxidant and anti-inflammatory properties, some compounds may simultaneously modulate NF-κB-dependent priming and activation signals required for NLRP3 inflammasome assembly, providing a mechanistic basis for their multi-target therapeutic actions [99,100]. This concept may extend beyond glial cells, as several nutraceuticals discussed in this review target upstream events known to promote neuronal NLRP3 activation, including mitochondrial dysfunction, ROS accumulation, redox imbalance, and NF-κB signaling [88,89]. Consequently, part of their neuroprotective and antinociceptive effects may result from the simultaneous modulation of neuronal and glial inflammasome signaling.

Although inflammation constitutes a physiological component of tissue repair following nerve injury, persistent immune activation and an imbalance between pro- and anti-inflammatory mediators promote maladaptive plasticity and chronic neuropathic pain [4,24,55,56,57,112]. Experimental studies demonstrate that targeting specific cytokines, stabilizing mast cells, reducing macrophage activation, or modulating autophagic pathways attenuates pain-related behaviors in preclinical models [44,49,59,64]. Nevertheless, the intricate interactions among neurons, immune cells, glial cells, redox signaling, and intracellular inflammatory pathways remain incompletely understood. Further elucidation of these neuroimmune mechanisms will be essential for developing more effective therapeutic strategies, including mechanism-based nutraceutical interventions, for neuropathic pain.

3.5. Sex Dimorphism in Neuroimmune Pain Signaling

Growing evidence indicates that neuroimmune mechanisms contributing to neuropathic pain differ substantially between males and females, with important implications for the development and translation of therapeutic strategies. Although neuroinflammation is recognized as a central driver of neuropathic pain in both sexes, the relative contribution of microglia, astrocytes, and adaptive immune cells appears to be sexually dimorphic [113,114].

In male rodents, spinal microglia play a dominant role in the initiation and maintenance of neuropathic pain. Following peripheral nerve injury, microglial activation is associated with increased expression of P2X4 receptors, activation of p38 MAPK, and release of pro-inflammatory mediators such as TNF-α, IL-1β, and BDNF, which contribute to central sensitization and pain hypersensitivity [14,27,71,73,74]. Pharmacological inhibition of microglial signaling or p38 MAPK effectively attenuates neuropathic pain behaviors in male animals, highlighting the importance of microglia-dependent pathways in males [115]. In contrast, female rodents appear to rely less on microglial-mediated signaling and more on adaptive immune responses. Sorge and co-workers [113] demonstrated that disruption of microglial signaling reversed mechanical allodynia in males but not in females, indicating that distinct neuroimmune mechanisms underlie pain hypersensitivity across sexes. In females, T lymphocytes appear to play a more prominent role in mediating nociceptive sensitization [113,114]. Furthermore, astrocytes, which are increasingly recognized as critical contributors to chronic pain maintenance [16,77,78,79,80], may have a greater influence on pain processing in females, although the underlying mechanisms remain incompletely understood [114,115].

These sex-dependent neuroimmune pathways have important implications for nutraceutical interventions targeting neuroinflammation and oxidative stress. Many compounds discussed in this review exert anti-neuropathic effects through modulation of microglial activation, MAPK signaling, cytokine production, and glia-neuron communication [96,100,101,102,110,111,116,117,118,119]. Because microglial p38 MAPK signaling appears to be particularly important in males, whereas T-cell- and astrocyte-dependent pathways may contribute more strongly in females, the efficacy and mechanisms of action of nutraceutical interventions may differ according to sex [113,114,115]. However, most preclinical studies investigating nutraceuticals in neuropathic pain have not systematically evaluated sex-specific responses. Consequently, future experimental and clinical studies should incorporate sex as a biological variable and determine whether nutraceutical interventions differentially modulate male- and female-specific neuroimmune pathways. Such an approach may improve translational relevance and support the development of more personalized nutraceutical strategies for neuropathic pain management.

4. The Role of Oxidative Stress in Neuropathic Pain

Oxidative stress or nitroxidative stress arises from a disruption in cellular oxidation-reduction (redox) homeostasis. This imbalance occurs when the production of ROS and/or RNS exceeds the capacity of endogenous antioxidant defense systems to neutralize and eliminate these reactive intermediates. Excessive ROS and RNS generation may result from mitochondrial dysfunction, altered cellular metabolism, environmental stressors, or impaired activity of enzymatic and non-enzymatic antioxidants [26]. Increased levels of ROS and RNS, and mitochondrial dysfunction have been reported to be involved in several types of pain [22,23,120]. In fact, in rodent models, the increased levels of ROS in the DRG and spinal cord were implicated in the development of neuropathic pain [121,122,123,124,125]. Changes in ROS levels have also been associated with the development of chronic pain in humans [126,127,128]. In neuropathic pain, the formation of ROS leads to significant damage to proteins, lipids, and DNA, eventually leading to mitochondrial dysfunction and cell death [129]. Furthermore, the oxidative environment can impair the function of ion channels and receptors involved in nociception, intensifying pain perception and perpetuating a continuous cycle of inflammation and pain [130,131,132,133].

4.1. Mitochondrial Dysfunction and ROS/RNS Production

Mitochondria are a major intracellular source of ROS, particularly during oxidative phosphorylation [134,135,136]. Under physiological conditions, electrons are transferred along the mitochondrial electron transport chain to support ATP synthesis. However, a small proportion of electrons can prematurely leak, mainly from complexes I and III, and react with molecular oxygen to generate superoxide radicals [134,135,137]. Superoxide can subsequently be converted into hydrogen peroxide (H₂O₂) by superoxide dismutases (SODs), while excessive superoxide may react with nitric oxide (NO) to form peroxynitrite, a highly RNS [138,139]. Thus, mitochondrial redox balance depends on the equilibrium between ROS/RNS generation and antioxidant defense systems, including manganese SOD (MnSOD), glutathione-related enzymes and proteins, catalase, and peroxiredoxins [138,140,141,142]. When mitochondrial function is impaired, electron leakage increases, antioxidant defenses may be overwhelmed, and ROS/RNS production is amplified [134,135,140].

In the context of neuropathic pain, injury-induced increases in ROS and RNS can impair mitochondrial function within nociceptive pathways, promoting further mitochondrial ROS release and the extrusion of DAMPs that activate inflammasomes and TLRs [23]. This bidirectional crosstalk establishes a self-perpetuating cycle of redox imbalance and neuroinflammation, driving the transcriptional upregulation of iNOS and NOXs that produce NO and ROS, further exacerbating oxidative and nitroxidative stress [23]. The resultant mitochondrial dysfunction contributes to neuronal hyperexcitability by impairing ATP synthesis and increasing superoxide production in the spinal cord [143,144]. The consequent energy deficiency disrupts the action of ion pumps, including the Na⁺/K⁺-ATPase, resulting in neuronal hyperexcitability and abnormal pain signaling [145]. Furthermore, dysfunctional mitochondria generate pro-apoptotic proteins, initiating neuronal apoptosis and increasing neuronal loss in pain pathways [89].

Impairment of the mitochondrial electron transport chain further promotes electron leakage, resulting in increased superoxide generation and triggering a broader cascade of ROS production. ROS generated in the spinal cord following nerve injury can enhance excitatory synaptic transmission in dorsal horn neurons via phosphorylation of NMDA receptors, phosphorylation and cell surface localization of AMPA receptors, and dysfunction or loss of gamma-aminobutyric acid neurons [125,146,147]. The production of superoxide via xanthine oxidase, together with superoxide and NO as precursors of peroxynitrite, has been shown to mediate central sensitization associated with NMDA receptor phosphorylation [148].

Peripheral nerve injury also promotes glutamate release, which activates NMDA receptors in the dorsal horn and contributes to the production of superoxide and NO. Superoxide reacts with NO to form peroxynitrite, which can perpetuate oxidative stress by promoting additional superoxide generation and inactivating intrinsic MnSOD through nitration. These processes contribute to spinal cord hypersensitivity and NMDA-mediated central sensitization [146,149]. Consistent with this mechanism, administration of SOD was shown to inhibit phosphorylation of spinal NMDA receptor subunit 1, thereby reducing mechanical allodynia and attenuating central sensitization in a rat spinal cord injury model [148].

Emerging nanozyme technologies, based on nanomaterials with enzyme-like activity, offer a promising strategy to counteract the complex mechanisms underlying neuropathic pain. By scavenging ROS, modulating inflammatory pathways, and reversing mitochondrial dysfunction, nanozymes may provide neuroprotection and pain relief [150].

Beyond impaired ATP production and increased electron leakage, mitochondrial dysfunction in neuropathic pain is closely linked to altered mitochondrial dynamics. Mitochondria continuously undergo fission and fusion, processes that regulate mitochondrial distribution, bioenergetic efficiency, calcium buffering, mitophagy, and cellular stress responses [151,152]. Mitochondrial fission is largely regulated by dynamin-related protein 1 (Drp1), which translocates from the cytosol to the outer mitochondrial membrane and promotes mitochondrial constriction and fragmentation through interactions with mitochondrial receptor/adaptor proteins, including Mff, Fis1, MiD49, and MiD51 [151,153]. Although physiological fission is necessary for mitochondrial turnover and quality control, excessive Drp1 activation after nerve injury may promote mitochondrial fragmentation, loss of mitochondrial membrane potential, impaired oxidative phosphorylation, and increased mitochondrial ROS production [154,155]. These events can contribute to nociceptor hyperexcitability, glial activation, and amplification of redox-sensitive inflammatory signaling pathways in neuropathic pain states [154,155]. In contrast, mitochondrial fusion, mediated primarily by mitofusin 1 and 2 (Mfn1/Mfn2) at the outer mitochondrial membrane and optic atrophy 1 (OPA1) at the inner mitochondrial membrane, preserves mitochondrial network integrity and supports mitochondrial function [151,152]. OPA1 is essential for cristae organization and respiratory chain efficiency, whereas Mfn2 also contributes to mitochondria–endoplasmic reticulum communication and calcium homeostasis [156,157,158]. Impairment of OPA1- or Mfn2-mediated fusion favors mitochondrial fragmentation, mitochondrial ROS generation, and mitochondrial DNA instability [151,156,157]. These mitochondrial alterations may facilitate the release of mitochondrial DAMPs, including oxidized mitochondrial DNA, which can activate pattern-recognition receptors and contribute to NLRP3 inflammasome priming and assembly in microglia and other immune-responsive cells [159,160,161]. Therefore, an imbalance favoring Drp1-mediated fission over OPA1/Mfn-mediated fusion may represent an important mechanistic bridge linking mitochondrial injury, ROS bursts, mitochondrial DNA release, inflammasome activation, and persistent neuroinflammation in neuropathic pain [154,155,159,160,161,162]. Restoration of mitochondrial fusion, improvement of mitophagy, or inhibition of excessive Drp1 activation may limit mitochondrial danger signaling and attenuate redox-driven neuroinflammatory pain mechanisms [155,162].

4.2. ROS/RNS in Neuropathic Pain: Major Species

ROS and RNS comprise a chemically diverse group of molecules that differ markedly in their reactivity, diffusion capacity, half-life, and biological functions [163]. A better understanding of the specific reactive species involved is essential for elucidating disease mechanisms and for developing targeted antioxidant therapies.

Among ROS, the superoxide anion (O₂^•−) is considered the primary radical generated following peripheral nerve injury. Superoxide originates predominantly from electron leakage at mitochondrial complexes I and III of the electron transport chain, NADPH oxidases (particularly NOX2 and NOX4), xanthine oxidase, and uncoupled NO synthase [136,164,165,166,167]. Although superoxide itself exhibits relatively limited membrane permeability and moderate reactivity, it serves as the precursor for several downstream reactive species implicated in neuronal dysfunction, neuroinflammation and neuropathic pain [168,169]. Superoxide is rapidly dismutated by SOD to form H₂O₂ [163]. Unlike superoxide, H₂O₂ is relatively stable, readily diffuses across biological membranes, and functions as an important intracellular signaling molecule [170]. Under physiological conditions, H₂O₂ participates in reversible redox signaling through selective oxidation of cysteine residues within regulatory proteins [170]. However, excessive H₂O₂ accumulation activates redox-sensitive pathways including NF-κB, and promotes microglia proliferation [171,172]. Additionally, in the presence of transition metals such as ferrous iron (Fe²⁺), H₂O₂ undergoes the Fenton reaction, producing the highly reactive hydroxyl radical (^•OH) [163]. Owing to its extremely short half-life and high reactivity, the hydroxyl radical reacts almost immediately with nearby lipids, proteins, carbohydrates, and nucleic acids, causing irreversible oxidative damage [163]. Unlike H₂O₂, hydroxyl radicals cannot be detoxified enzymatically [173] and therefore represent one of the most destructive ROS contributing to mitochondrial dysfunction and neuronal degeneration during neuropathic pain [93].

Among RNS, NO is the principal signaling molecule involved in neuropathic pain. NO is synthesized by neuronal (nNOS), endothelial (eNOS), and iNOS. While constitutive NO production regulates neurotransmission and vascular homeostasis, excessive NO generated by iNOS during neuroinflammation contributes to pathological redox signaling [23,26]. In particular, NO rapidly reacts with superoxide at diffusion-limited rates to generate peroxynitrite (ONOO⁻), one of the most cytotoxic RNS [22,26]. Peroxynitrite promotes tyrosine nitration, lipid peroxidation, DNA damage, mitochondrial dysfunction, and nitration-mediated inactivation of mitochondrial MnSOD, thereby amplifying oxidative stress and sustaining central sensitization [22,23]. Experimental studies have consistently identified peroxynitrite as a major mediator linking oxidative stress to persistent neuropathic pain [23,169].

In addition to primary ROS and RNS, increasing attention has been directed toward secondary oxidation products that function as bioactive mediators rather than merely markers of oxidative damage. Lipid peroxidation generates highly reactive aldehydes such as 4-hydroxynonenal (4-HNE) and 4-oxo-2-nonenal (4-ONE), which covalently modify ion channels, mitochondrial proteins, transcription factors, and inflammatory signaling molecules involved in nociceptive processing [174,175]. Similarly, hypochlorous acid (HOCl), generated by myeloperoxidase in activated neutrophils and macrophages, contributes to oxidative protein modification and may participate in inflammatory pain signaling [176].

Because ROS and RNS are highly reactive and generally exhibit half-lives ranging from nanoseconds to milliseconds, their direct measurement remains technically challenging. Consequently, many studies investigating oxidative stress in neuropathic pain rely on indirect biomarkers, including malondialdehyde (MDA), 4-HNE, protein carbonyls, 3-nitrotyrosine, 8-hydroxy-2′-deoxyguanosine (8-OHdG), glutathione redox status (GSH/GSSG), and antioxidant enzyme activities (SOD, catalase and glutathione peroxidase). For more detailed information on approaches to measuring ROS/RNS and oxidative damage, see Ref. [177]. While these biomarkers provide valuable information regarding cumulative oxidative damage, they do not identify the specific reactive species responsible nor their temporal or subcellular distribution [177,178].

4.3. Oxidative Stress and Modulation of TRP and Voltage-Gated Ion Channels

The oxidative environment modulates the activity of ion channels critical for nociception such as transient receptor potential (TRP) ion channels, which are sensitive to redox modifications [179]. Specifically, the intracellular redox status can significantly alter the gating properties of these ion channels, leading to increased neuronal excitability and pain hypersensitivity [180]. The TRP ion channels are extensively distributed in the central nervous system and peripheral nervous system, and are highly permeable to Ca²⁺, also transporting other cations such as Na⁺ and Mg²⁺ [181]. TRP channels represent an extended family composed of 28 members, and are classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (no mechanoreceptor) [182]. Among these, TRPA, TRPM, and TRPV have been associated with neuropathic pain [183]. ROS generated in the spinal cord following nerve injury can enhance excitatory synaptic transmission in dorsal horn neurons via activation of TRPV1 and TRPA1, ion channels known to be involved in membrane depolarization and consequent nociceptive sensitization in the spinal cord in chronic pain after spinal cord injury [184,185]. Mitochondrial-derived ROS are also required for the activation of TRPV1 channels following peripheral sensory axotomy, a process that can be blocked by ROS scavenging, and contributes to calcium entry preceding neuronal degeneration [132]. Furthermore, the thiol redox system, including glutathione (GSH) and N-acetylcysteine, exerts protective effects on peripheral pain by inhibiting cysteine oxidation on TRPA1 and TRPM2 channels [131]. Similarly, modulation of TRPV1 activity in DRG neurons reduces calcium influx, prevents mitochondrial membrane potential damage, and decreases mitochondrial ROS levels following nerve injury [185]. This process specifically involves the opening of the mitochondrial permeability transition pore (mPTP), which exacerbates neuronal degeneration and death by affecting energy metabolism, inducing oxidative damage, disrupting intracellular calcium homeostasis, and triggering apoptosis and necrosis [186].

Beyond TRP channels, voltage-gated ion channels also represent critical molecular determinants of neuronal hyperexcitability in neuropathic pain. Voltage-gated sodium channels, particularly Nav1.7 and Nav1.8, are frequently upregulated or functionally sensitized following peripheral nerve injury, promoting ectopic action potential generation and sustained nociceptor excitability [187,188]. Conversely, reduced activity or expression of voltage-gated potassium (Kv) channels impairs membrane repolarization, further enhancing spontaneous neuronal firing [188,189]. Oxidative and nitrosative stress can directly modulate these channels through redox-dependent post-translational modifications, thereby amplifying nociceptive signaling [93]. Although the evidence remains more extensive for TRP channels, several nutraceuticals discussed in this review have also been reported to influence voltage-gated sodium and potassium channel activity either directly or indirectly through their antioxidant and anti-inflammatory properties, contributing to the attenuation of neuronal hyperexcitability.

5. Crosstalk Between Redox Imbalance and Neuroinflammation

Oxidative stress and neuroinflammation form a complex network of reciprocal interactions, each acting as both a cause and a consequence of the other [190]. Persistent nociceptive input induces maladaptive changes within the central nervous system, including enhanced neuronal excitability, activation of microglia and astrocytes, and increased production of pro-inflammatory cytokines [191]. Mitochondrial dysfunction in sensory neurons contributes to the transition from acute to chronic pain by disrupting cellular redox homeostasis. Transient inflammation can induce hyperalgesic sensitization through increased expression of mitochondrial ATPSc-KMT (formerly FAM173B), resulting in metabolic disturbances, characterized by mitochondrial hyperpolarization and enhanced production of ROS [143,192]. Excess ROS generated by the mitochondrial electron transport chain activates pro-inflammatory signaling cascades and stimulates microglial activation, thereby sustaining inflammatory pain states [143]. Moreover, ATPSc-KMT promotes the ROS-dependent release of glial-activating mediators, including IL-6 and TNF-α, further amplifying neuroinflammatory responses [143].

Metabolic reprogramming of glial cells represents another important link between oxidative stress and neuroinflammation. During neuropathic pain development, microglia and astrocytes undergo a metabolic shift from oxidative phosphorylation toward glycolysis [193]. This transition promotes lactate accumulation, which enhances inflammatory signaling through activation of the NF-κB/IL-8 pathway, increases ROS production, and upregulates genes involved in oxidative stress and pro-inflammatory responses [194,195]. Likewise, spinal nerve transection injury induced NOX2-dependent ROS generation in spinal microglia, resulting in increased expression of TNF-α and IL-1β, both of which contribute to neuropathic pain initiation [196]. Consistent with this mechanism, inhibition of ROS-induced p38 MAPK and ERK activation in microglia alleviates neuropathic pain following spinal cord injury in experimental models [197]. Conversely, IL-10 and transforming growth factor (TGF)-β1 suppress microglial ROS production through NOX2 inhibition, while antioxidant treatment or genetic deletion of NOX enhances the expression of anti-inflammatory cytokines [164,198,199,200,201]. Thus, activated glial cells function both as sources and targets of ROS and inflammatory mediators, establishing a self-perpetuating feed-forward cycle that sustains oxidative stress, neuroinflammation, and neuropathic pain.

Beyond alterations in cellular metabolism and ROS generation, dysregulation of mitochondrial dynamics further amplifies the reciprocal interactions between oxidative stress and neuroinflammation. Excessive Drp1-dependent mitochondrial fission promotes mitochondrial fragmentation and enhances mitochondrial ROS production, whereas impaired OPA1- and Mfn2-mediated fusion compromises respiratory efficiency, calcium homeostasis, and mitochondrial DNA stability [151,154,155,156,157,158]. These alterations can promote the cytosolic release of mitochondrial DNA and other DAMPs, thereby facilitating activation of innate immune pathways, including TLR signaling and the NLRP3 inflammasome [159,160,161]. In microglia, these events reinforce NF-κB-dependent inflammasome priming and caspase-1-mediated maturation of IL-1β, creating a vicious cycle in which mitochondrial dysfunction, oxidative stress, inflammasome activation, and neuroinflammation mutually sustain neuropathic pain [154,159,162].

At the transcriptional level, the interplay between oxidative stress and neuroinflammation is further coordinated through reciprocal regulation of the nuclear factor erythroid 2-related (Nrf2) and NF-κB signaling pathways. Although often considered distinct signaling pathways, accumulating evidence indicates that these transcriptional programs are functionally interconnected and compete for limiting co-activators, including CREB-binding protein (CBP) and p300 [202,203]. Under conditions of persistent inflammation, NF-κB preferentially recruits CBP/p300 to pro-inflammatory gene promoters, enhancing the expression of cytokines, chemokines, COX-2 and iNOS, while simultaneously limiting Nrf2-dependent transcription of antioxidant genes [203,204]. Conversely, activation of Nrf2 promotes the expression of antioxidant and cytoprotective genes, including HO-1, NQO1, SOD, and other redox-regulating enzymes, while indirectly suppressing NF-κB signaling through reduction in oxidative stress and interference with inflammatory pathways [202,204]. Thus, the balance between Nrf2- and NF-κB-dependent transcriptional programs represents an important molecular switch linking oxidative stress and neuroinflammation during neuropathic pain.

Importantly, the interplay between oxidative stress and neuroinflammation is not static but evolves throughout neuropathic pain progression. During the early phase following nerve injury, tissue damage induces the release of DAMPs, activation of Schwann cells, infiltration of neutrophils, macrophages, and T cells, together with rapid spinal microglial activation, thereby promoting peripheral and central sensitization [4,17,71]. As neuropathic pain progresses to a chronic state, persistent astrocyte activation, sustained cytokine production, oxidative stress, mitochondrial dysfunction, NLRP3 inflammasome signaling, and maladaptive neuroplastic changes become increasingly important in maintaining pain hypersensitivity [16,80,205]. This temporal evolution suggests that the molecular mechanisms underlying pain initiation differ, at least in part, from those responsible for pain maintenance, with important implications for therapeutic intervention.

Although much of the mechanistic evidence linking oxidative stress and neuroinflammation to neuropathic pain derives from studies of the spinal cord and DRG, chronic pain is increasingly recognized as a disorder involving distributed supraspinal networks [16,37]. Brain regions including the amygdala, prefrontal cortex (PFC), anterior cingulate cortex (ACC), hippocampus, and thalamus undergo neuroplastic, neuroimmune, and redox-related alterations that contribute not only to nociceptive processing but also to the emotional, affective, and cognitive dimensions of chronic pain [16,35,191]. Within these regions, activation of microglia and astrocytes, increased production of pro-inflammatory cytokines, oxidative stress, and alterations in excitatory and inhibitory neurotransmission have been associated with pain persistence, anxiety-like behaviors, depressive symptoms, and cognitive dysfunction [16,35,37]. These observations indicate that oxidative stress and neuroinflammation extend beyond spinal nociceptive circuits to involve broader brain networks that participate in pain perception and chronification.

Because these mechanisms are highly interconnected, therapeutic strategies targeting a single pathway may be insufficient to interrupt neuropathic pain chronification. Nutraceuticals with combined antioxidant and anti-inflammatory properties are therefore particularly attractive, as they may simultaneously reduce ROS/RNS accumulation, preserve mitochondrial homeostasis, inhibit redox-sensitive inflammatory signaling, limit NLRP3 inflammasome activation, and attenuate glial activation (Figure 1). Although most experimental evidence has focused on peripheral and spinal mechanisms, accumulating studies indicate that several nutraceuticals discussed in this review may also modulate neuroinflammatory and redox-sensitive pathways within supraspinal regions, suggesting that their therapeutic actions could extend to brain circuits involved in the affective and cognitive dimensions of chronic pain [16,118]. However, it remains unclear whether these effects result from direct modulation of supraspinal targets or occur secondary to reduced peripheral and spinal neuroinflammation [35,37]. Future studies should therefore determine the relative contribution of peripheral, spinal, and supraspinal mechanisms to the therapeutic actions of nutraceuticals. Consistent with this concept, several nutraceuticals discussed in this review have been reported to activate Nrf2 while suppressing NF-κB signaling, suggesting that restoration of the balance between these transcriptional programs contributes to their multi-target therapeutic effects [119,204]. Collectively, these findings support the concept that simultaneous modulation of oxidative stress and neuroimmune signaling represents a promising strategy for complementary neuropathic pain management.

Figure 1. Integrated mechanisms linking mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal sensitization in neuropathic pain. Peripheral nerve injury initiates neuroimmune activation and mitochondrial dysfunction, resulting in excessive production of reactive oxygen and nitrogen species (ROS/RNS), impaired ATP production, altered mitochondrial dynamics (increased Drp1-mediated fission and reduced Mfn1/Mfn2/OPA1-mediated fusion), and release of mitochondrial danger-associated molecular patterns (mtDNA). ROS and mitochondrial signals activate redox-sensitive pathways, including NF-κB, MAPKs (p38, ERK, JNK), and the NLRP3 inflammasome, promoting production of TNF-α, IL-1β, IL-6, IL-18, and other inflammatory mediators by microglia, astrocytes, macrophages, satellite glial cells, and Schwann cells. These pathways form self-amplifying feed-forward loops that sustain oxidative stress, mitochondrial dysfunction, glial activation, and neuronal hyperexcitability, leading to peripheral and central sensitization through modulation of NMDA, AMPA, and ion channel signaling. 5-HT, serotonin; ASC, apoptosis-associated speck-like protein containing a CARD); AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CCL2, chemokine (C-C motif) ligand 2; CGRP, calcitonin gene-related peptide; COX-2, cyclooxygenase 2; CSF-1, colony-stimulating factor 1; Cx43, connexin 43; CXCL1, chemokine (C-X-C motif) ligand-1; CXCL12, chemokine (C-X-C motif) ligand-12; Drp1, dynamin-related protein 1; ERK, extracellular signal-regulated kinase; IFN-I, type I interferon; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-17, interleukin-17; IL-18, interleukin-18; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; Kv, voltage-gated potassium channel; MAPKs, mitogen-activated protein kinases; MFN1, mitofusin-1; MFN2, mitofusin-2; mtDNA, mitochondrial DNA; Nav1.7, voltage-gated sodium channel 1.7; Nav1.8, voltage-gated sodium channel 1.8; NF-κB, nuclear factor kappa B; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NO, nitric oxide; p38 MAPK, p38 mitogen-activated protein kinase; Panx1, pannexin-1; PGE2, prostaglandin E2; SGCs, satellite glial cells; TLRs, toll-like receptors; TNF-α, tumor necrosis factor alpha; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid 1; Symbols: → denotes activation/stimulation; ↑ denotes upregulation/increase; and ↓ denotes downregulation/decrease.

6. Nutraceutical Interventions: Evidence and Mechanisms

Conventional pharmacological therapies for neuropathic pain, including antidepressants, anticonvulsants, and opioids, often provide only partial symptom relief and are frequently associated with adverse effects, poor tolerability, and long-term safety concerns. These limitations have stimulated increasing interest in complementary therapeutic strategies, particularly nutraceuticals and dietary interventions [206,207,208]. Nutraceuticals comprise a diverse group of bioactive compounds derived from foods and food sources, including vitamins, minerals, fatty acids, polyphenols, amino acids, and herbal products. Their therapeutic potential is largely attributed to their pleiotropic actions on multiple molecular targets. Increasing evidence indicates that these compounds may modulate chronic pain states, including neuropathic pain, through the regulation of neuroinflammation, oxidative stress, and neuronal signaling pathways [30,31,33].

Many bioactive compounds suppress key intracellular signaling pathways involved in neuroinflammation, particularly NF-κB and MAPKs, thereby attenuating glial activation and inflammatory mediator production [209]. Since neuroinflammation is a central driver of neuropathic pain, modulation of these pathways represents a major mechanism underlying the analgesic effects of nutraceuticals [207]. Oxidative stress constitutes another fundamental contributor to neuropathic pain by promoting mitochondrial dysfunction, neuronal damage, and apoptosis. Nutraceuticals with antioxidant properties may counteract these processes by scavenging ROS, enhancing endogenous antioxidant defenses, and limiting oxidative damage [210]. In addition, several compounds appear to preserve mitochondrial homeostasis by promoting autophagy and mitophagy, thereby facilitating the removal of dysfunctional mitochondria and preventing sustained oxidative stress [32]. This mechanism is particularly relevant because defective mitophagy contributes to excessive ROS production, activation of the NLRP3 inflammasome, and persistent neuroinflammation [211]. Activation of signaling pathways such as AMP-activated protein kinase (AMPK)/SIRT1 may further enhance mitochondrial quality control, complementing the antioxidant and anti-inflammatory actions of nutraceuticals through maintenance of mitochondrial integrity [32,212]. Beyond these effects, several dietary bioactive compounds also modulate nociceptive transmission through interactions with TRP channels, voltage-gated ion channels, and signaling pathways involved in neuronal survival and synaptic plasticity [213,214,215,216,217,218,219].

Evidence from preclinical studies, supported by an increasing number of clinical investigations, indicates that numerous nutraceuticals exert anti-neuropathic effects through multiple complementary mechanisms [30,31,188,206,220,221,222]. Although much of the available evidence originates from in vitro and animal studies, these investigations consistently demonstrate attenuation of key manifestations of neuropathic pain, including mechanical allodynia, mechanical and thermal hyperalgesia, and cold hypersensitivity [209]. However, these reflexive pain-related behaviors should be distinguished from indices of structural and functional recovery, such as motor performance, nerve conduction, axonal regeneration, remyelination, and functional recovery scores. Whereas improvements in pain hypersensitivity primarily reflect reduced peripheral and central sensitization, restoration of neural function depends on additional regenerative and neuroprotective mechanisms that only partially overlap with analgesic pathways. Consequently, improvements in nociceptive behavior should not be interpreted as evidence of neural repair unless supported by appropriate structural or functional assessments [4,17].

Clinical studies investigating dietary interventions, vitamin supplementation, and specific nutraceuticals have also increased in recent years, particularly in patients who respond poorly or experience adverse effects with conventional pharmacological therapies [206]. Although these studies provide encouraging findings, the available evidence remains limited, emphasizing the need for larger, well-designed randomized controlled trials to establish efficacy, determine optimal dosing regimens, and evaluate long-term safety [30,188].

Despite the growing mechanistic evidence supporting nutraceutical interventions, an important limitation concerns the uncertainty regarding target engagement within the central nervous system. Many phytochemicals exhibit poor oral bioavailability because of limited intestinal absorption, extensive first-pass metabolism, and rapid elimination [223,224,225]. Consequently, although numerous experimental studies report modulation of signaling pathways such as NF-κB, MAPKs, JAK/STAT, and the NLRP3 inflammasome, direct modulation of these intracellular targets within spinal cord or brain tissues cannot always be assumed [223,226]. Instead, some of the observed biological effects may result from indirect mechanisms, including attenuation of systemic inflammation, modulation of peripheral immune responses, regulation of gut microbiota composition, production of bioactive microbial metabolites, and activation of gut–brain neuroimmune pathways [226,227]. These systemic effects may ultimately influence glial activation, cytokine production, and neuroinflammatory signaling despite limited penetration of the parent compounds into the central nervous system. This concept is particularly relevant for polyphenol-rich nutraceuticals. Because many dietary polyphenols display low oral bioavailability, a substantial proportion reaches the colon, where they are metabolized by intestinal microorganisms into smaller phenolic metabolites that frequently exhibit greater absorption and biological activity than the parent compound [226,228]. In parallel, polyphenols may reshape gut microbial communities by promoting beneficial bacterial taxa while suppressing pro-inflammatory populations [228]. These interactions may influence gut–brain communication through microbial metabolites, particularly short-chain fatty acids, immune mediators, and vagal signaling pathways, thereby modulating neuroinflammation and pain processing [227,229,230]. Although direct evidence in neuropathic pain remains limited, the gut microbiota–brain axis represents a plausible complementary mechanism contributing to the neuroprotective and antinociceptive effects of several polyphenol-rich nutraceuticals.

These considerations are particularly important when interpreting the multi-target actions attributed to nutraceuticals, as improvements in pain-related outcomes do not necessarily demonstrate direct modulation of molecular pathways within the central nervous system. Therefore, future studies should integrate pharmacokinetic analyses, blood–brain barrier permeability assessments, tissue exposure measurements, target-engagement biomarkers, and characterization of gut microbiota-derived metabolites to better establish whether modulation of neuroinflammatory pathways reflects direct central nervous system activity, indirect systemic and microbiota-mediated mechanisms, or a combination of these.

Beyond issues related to bioavailability and target engagement, dose–response relationships also deserve careful consideration. Although several experimental studies report dose-dependent beneficial effects within the investigated ranges, increasing evidence indicates that some phytochemicals exhibit hormetic dose–response patterns characterized by U-shaped or inverted U-shaped curves. Under these conditions, higher doses may lose efficacy or even induce pro-oxidant or off-target effects [231,232]. Therefore, defining optimal therapeutic windows should represent a major objective of future preclinical and clinical investigations.

Another important aspect concerns the interpretation of the multi-target actions attributed to nutraceuticals. Throughout this review, the terms “multi-target” and “pleiotropic” refer to the capacity of individual compounds to modulate multiple molecular pathways involved in neuropathic pain. However, these properties should not be interpreted as evidence of pharmacological synergy. Synergy requires demonstration that the combined effect of two interventions exceeds the sum of their individual effects and must be established using dedicated pharmacodynamic approaches [233]. Although several studies report greater efficacy when nutraceuticals are combined with other bioactive compounds or conventional therapies, most fail to distinguish synergistic interactions from simple additive effects [234,235,236,237,238,239,240]. Future investigations should therefore incorporate appropriate experimental designs and analytical methods to discriminate synergy from additivity, thereby facilitating the rational development of evidence-based combination therapies.

Given the diversity of nutraceuticals investigated in neuropathic pain and their distinct mechanisms of action, the following sections summarize the major classes of bioactive compounds, highlighting their principal molecular targets together with the available preclinical and clinical evidence.

6.1. Phytochemicals

Phytochemicals are naturally occurring bioactive compounds found in plants and are widely recognized for their potential health-promoting effects when consumed as part of the diet [241,242]. They are commonly classified as primary or secondary metabolites. Primary metabolites, including carbohydrates, proteins, and lipids, are directly involved in essential processes such as growth, photosynthesis, and respiration. In contrast, secondary metabolites are not required for basic metabolism but contribute to plant defense against pathogens, herbivores, and environmental stressors [243]. Secondary metabolites, including flavonoids, terpenoids, alkaloids, phenolic acids, and glucosinolates, have attracted considerable interest because of their antioxidant, anti-inflammatory, and neuromodulatory activities. These properties are particularly relevant in neuropathic pain, where oxidative stress, glial activation, cytokine release, mitochondrial dysfunction, and maladaptive neuronal plasticity contribute to persistent pain states [242].

6.1.1. Polyphenols and Related Phenolic Compounds

Polyphenols comprise a diverse group of plant-derived secondary metabolites characterized by one or more phenolic rings and recognized for their broad biological activity [244,245]. Among these compounds, flavonoids and related phenolics have received particular attention in neuropathic pain research because they can simultaneously target neuroinflammation, oxidative stress, mitochondrial dysfunction, glial activation, and neuronal sensitization. Since these mechanisms interact closely in neuropathic pain pathogenesis, polyphenols represent attractive multi-target nutraceutical candidates [246].

Curcumin, the principal bioactive constituent of turmeric, is among the most extensively investigated phenolic compounds in experimental neuropathic pain. Across several models, including spared nerve injury, CCI, diabetic neuropathy (DN), chemotherapy-induced peripheral neuropathy (CIPN), and sciatic nerve injury, curcumin attenuates mechanical allodynia and thermal hyperalgesia, and may improve neuronal survival [96,247,248,249,250,251]. These effects are initiated by primary pharmacological actions, specifically the inhibition of janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling, CX3CR1-mediated microglial signaling, and NALP1 inflammasome activation. This upstream modulation subsequently triggers a downstream transcriptional cascade that reduces the expression of secondary pro-inflammatory mediators, such as TNF-α and IL-1β [96,252,253,254,255]. Curcumin also enhances endogenous antioxidant responses by activating Nrf2 signaling, reducing NADPH oxidase activity, decreasing lipid peroxidation, and restoring antioxidant enzyme activity [249,250,251]. In addition, modulation of tropomyosin receptor kinase A (TrkA)/phosphoinositide 3-kinase (PI3K)/Akt signaling and glial polarization may contribute to its neuroprotective and anti-sensitizing effects [116,247,256]. Beyond signaling cascades, curcumin is one of the best-characterized examples, acting as an inhibitor of CBP/p300 histone acetyltransferase (HAT), thereby reducing histone acetylation and the transcription of pro-inflammatory and pro-nociceptive genes, including Cox-2 and Bdnf [253,257]. In addition, curcumin has been shown to regulate DNA methylation, histone modifications, and non-coding RNAs, while also suppressing inflammasome activation through inhibition of NF-κB- and ROS-dependent pathways [258].

Quercetin has demonstrated anti-neuropathic activity across DN, CIPN, and CCI models. Its mechanism is initiated by primary pharmacological actions on upstream signaling nodes, specifically the direct activation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator 1 alpha (PGC-1α) pathway and the inhibition of the TLR4/MyD88 complex and mast cell activation. These initial interactions subsequently trigger downstream homeostatic feedback, including the suppression of MAPK and NF-κB signaling cascades and the activation of the Nrf2/heme oxygenase (HO)-1 antioxidant defense system [97,248,259,260,261,262]. Furthermore, quercetin may promote structural nerve recovery by modulating upstream axonal guidance factors (Slit-2 and Netrin-1), which subsequently inhibits the pro-degenerative Rho/ROCK signaling pathway [259].

Other flavonoids have demonstrated beneficial effects in experimental neuropathic pain. Naringenin reduces mechanical allodynia and thermal hyperalgesia through inhibition of microglial and astrocytic activation, suppression of pro-inflammatory cytokines, enhancement of antioxidant defenses, and reduction in central sensitization [263,264,265,266,267]. Epigallocatechin gallate (EGCG), the major catechin in green tea, exerts neuroprotective effects through modulation of NF-κB/MAPK signaling, enhancement of insulin-like growth factor (IGF)-1-related pathways, attenuation of oxidative stress, and regulation of microglial activation in DN and CIPN models [98,268,269,270]. Genistein has likewise been reported to reduce pain hypersensitivity by decreasing oxidative stress and inflammatory cytokine production while supporting axonal regeneration and remyelination, as reflected by increased growth-associated protein (GAP)-43 and myelin basic protein (MBP) expression [271,272,273,274].

Overall, polyphenols appear to exert their anti-neuropathic effects through convergent regulation of redox-sensitive inflammatory pathways, glial activation, mitochondrial homeostasis, neuronal survival, and regenerative processes (Table 1). Their ability to simultaneously modulate NF-κB, MAPKs, Nrf2, inflammasome activity, and neurotrophic signaling supports their relevance as multi-target interventions. Nevertheless, most evidence remains preclinical, and further clinical studies are required to determine optimal formulations, dosing regimens, bioavailability, safety, and long-term efficacy.

Table 1. Polyphenols and related phenolic compounds with demonstrated effects in preclinical studies of neuropathic pain.

Nutraceutical	Source	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
Curcumin	Turmeric	Spared nerve injury	Male BALB/c mice	30–120 mg/kg (i.p.)	Primary ↓ NALP1 inflammasome and JAK2/STAT3 signaling → downstream ↓ spinal IL-1β and mechanical/cold allodynia.	[96]
		Sciatic nerve injury	Male Sprague–Dawley rats and PC-12 cells	100 mg/kg/day (i.p., in vivo) and 200 µM (in vitro)	Upstream ↑ TrkA and PI3K/Akt signaling, subsequently ↑ NGF levels to provide neuroprotection.	[247]
		CIPN (Oxaliplatin-induced)	Male Sprague–Dawley rats and male C57BL/6 J mice	10–50 mg/kg/day (i.p. or p.o.)	↓ Mechanical and cold allodynia; ↑ nerve function; initial ↓ spinal GSK-3β and NF-κB, → downstream ↓ TNF-α, IL-1β, and IL-6, while ↑ secondary Nrf2-mediated antioxidant responses; ↓ oxidative damage and inflammation.	[249,275]
		DN	Male Sprague–Dawley rats and male Laka mice	10–200 mg/kg/day (p.o.)	↓ Mechanical and thermal hypersensitivity via ↓ NADPH oxidase subunits (gp91phox, p47phox), ↓ oxidative/nitrosative markers (H2O2, MDA, NO), and ↑ antioxidant defense (SOD).	[239,250,254,255,276]
		CCI	Male Sprague–Dawley rats and male Wistar rats	20–100 mg/kg/day (i.p. or p.o.)	↑ Pain threshold; ↓ allodynia; ↓ spinal NF-κB and CX3CR1; ↓ neuroinflammation/central sensitization; ↓ TNF-α/TNFR1, BDNF, COX-2 via p300/CBP HAT inhibition (epigenetic downregulation of pro-nociceptive genes); ↓ thermal hyperalgesia; modulation of microglial activation toward a less pro-inflammatory phenotype, with ↓ cytokine release; ↓ p-ERK, p-JNK, and p-NR1.	[116,252,253,256,277]
Quercetin	Apples, onions, capers	DN	Male Sprague–Dawley rats and RSC96 Schwann cells	30 and 60 mg/kg/day (p.o., in vivo) and 5–20 µM (RSC96 Schwann cells, in vitro); 2.5–10 mmol/L (DRG neurons, in vitro)	Upstream modulation of primary axonal guidance factors (Slit-2, Netrin-1) → downstream ↓ Rho/ROCK-mediated degeneration; primary inhibition of the TLR4/MyD88 complex → downstream suppression of NF-κB-mediated pro-inflammatory signaling and Nrf2-driven neuroprotection; upstream ↑ AMPK/PGC-1α axis → ↑ mitochondrial biogenesis and energy metabolism; ↓ neurodegeneration and peripheral sensitization; ↓ mechanical allodynia.	[97,248,259,260]
		CIPN (Vincristine-, paclitaxel-, and oxaliplatin-induced)	Male Sprague–Dawley rats and male Swiss mice	20–100 mg/kg/day (i.p. or p.o.)	↓ Neuroinflammation, oxidative stress, and neuronal injury via ↓ caspase-3 (apoptosis), NF-κB (inflammation), and ATF-6 (ER stress); ↑ Nrf2 antioxidant and Akt pro-survival signaling; ↓ mechanical allodynia and thermal hyperalgesia via primary mast cell stabilization and ↓ PKCε, which subsequently blocks TRPV1 activation and leads to a secondary ↓ oxidative stress and lipid peroxidation (ROS scavenging); ↓ inflammatory mediator release.	[278,279,280]
		CCI	Male Sprague–Dawley rats	10–120 mg/kg/day (p.o.)	↓ Neuroinflammation and nociceptive sensitization via ↑ AMPK and ↓ MAPK signaling (p38, p-ERK, p-JNK); ↓ neuroinflammatory activation and peripheral/central sensitization via TLR signaling inhibition.	[261,262]
Naringenin	Citrus fruits	DN	Male Wistar rats	10–100 mg/kg/day (p.o.)	↓ Mechanical allodynia and thermal hyperalgesia; improved nerve function; ↓ oxidative stress markers (MDA); ↑ antioxidant defenses (SOD, CAT, GSH); ↓ inflammatory mediators (TNF-α, IL-1β, IL-6) in neural tissue; ↓ oxidative/nitrosative stress; ↓ cytokines and MMP-9; ↓ neuroinflammation and peripheral/central sensitization.	[263,265]
		Spinal nerve ligation	Male Sprague–Dawley rats	50–200 mg/kg/day (i.t.)	↓ Mechanical allodynia and thermal hyperalgesia; ↓ spinal astrocyte and microglia activation (↓ GFAP, Mac-1); ↓ pro-inflammatory mediators (TNF-α, IL-1β, MCP-1).	[264]
		Compression spinal cord injury	Male Wistar rats	5–15 mM in a volume of 20 µL (i.t.)	↓ Oxidative stress and neuroinflammation; ↑ antioxidant defenses (GSH, CAT); ↓ MMP-9 and ↑ MMP-2 activity; ↑ neuronal survival; ↓ central sensitization.	[266]
		CIPN (Paclitaxel-induced)	Male and female CD-1 mice	5–50 mg/kg/day (i.p.)	↓ CGRP-mediated neuroimmune signaling; ↓ macrophage and glial activation; ↓ NF-κB signaling; modulation of microglial activation state; ↓ neuroinflammation and neuronal sensitization.	[267]
EGCG and EGCG derivatives	Green tea	CCI	Female Balb-c mice	10–100 mg/kg/day (i.p.)	↓ Thermal hyperalgesia via ↓ FASN activity and ↓ NF-κB–mediated cytokines (TNF-α, IL-1β, IL-6) acutely; ↓ chronic pain via ↓ synaptic plasma membrane levels of NMDAR2B.	[98]
		CIPN (Oxaliplatin-induced)	Male C57BL/6 J mice	50 mg/kg/day (i.p.)	↓ Mechanical allodynia and sensory dysfunction via ↑ IGF-1 signaling, ↓ neuroinflammation, ↓ microglial/macrophage activation, and inhibition of NF-κB/MAPK pathways.	[268]
		DN	Male Swiss rats and male C57BL/6J mice	20–25 mg/kg/day (i.p. or p.o.) and 2 μg/day (i.t.)	↓ Mechanical allodynia and thermal hyperalgesia; improved metabolic profile (↓ MDA; ↑ SOD, CAT, GSH); ↓ neuroinflammation (↓ TNF-α, IL-1β, IL-6); ↓ NF-κB activation; metabolic modulation (↓ blood glucose, ↓ serum lipids); ↑ IGF-1 signaling in spinal microglia; ↓ ROS and oxidative stress; modulation of microglial activation state.	[269,270]
Genistein	Soybeans	DN	Male C57BL/6J mice	3 and 6 mg/kg/day (s.c.)	↓ Mechanical allodynia via ↓ neuroinflammation (↓ TNF-α, IL-1β, IL-6 in the sciatic nerve); ↓ oxidative stress (↓ ROS, ↓ MDA; ↑ SOD, ↑ GSH/GSSG ratio); ↑ neurotrophic support (↑ NGF); and improvement of vascular function (↑ eNOS, ↓ iNOS).	[271]
		Sciatic nerve crush and transection	Male Sprague–Dawley rat	20 mg/kg/day (i.p.)	↑ Functional recovery; ↓ mechanical hypersensitivity via ↓ neuroinflammation (↓ IL-1β, TNF-α); ↑ axonal regeneration (↑ GAP-43) and remyelination (↑ MBP).	[272]
		CIPN (Paclitaxel-induced)	Male Wistar rats	10 and 20 mg/kg/day (p.o.)	↓ Thermal hyperalgesia (Tail flick, Eddy’s hot plate) and ↓ cold allodynia (Tail immersion test); preservation of neuronal health against chemotherapy-induced (paclitaxel) neurotoxicity.	[273]
		CCI	Male C57BL/6J mice	1–30 mg/kg/day (s.c.)	↓ Mechanical allodynia and thermal hyperalgesia via ↓ neuroinflammation (↓ IL-1β, IL-6), ↓ oxidative stress (↓ ROS, ↓ MDA), inhibition of peripheral NF-κB activation, and ↑ antioxidant enzyme activity (GPX, CAT).	[274]

Abbreviations: AMPK, AMP-activated protein kinase; ATF-6, activating transcription factor 6; BDNF, brain-derived neurotrophic factor; CAT, catalase; CBP, CREB-binding protein; CCI, chronic constriction injury; CGRP, calcitonin gene-related peptide; CIPN, chemotherapy-induced peripheral neuropathy; COX-2, cyclooxygenase-2; CX3CR1, CX3C chemokine receptor 1; DN, diabetic neuropathy; DRG, dorsal root ganglion; EGCG, epigallocatechin gallate; ERK, extracellular signal-regulated kinase; GFAP, glial fibrillary acidic protein; GSH, reduced glutathione; GSK-3β, glycogen synthase kinase-3 beta; GSSG, oxidized glutathione; HAT, histone acetyltransferase; HO-1, heme oxygenase-1; IGF-1, insulin-like growth factor 1; IL, interleukin; i.p., intraperitoneal; i.t., intrathecal; JAK2, janus kinase 2; JNK, c-Jun N-terminal kinase; Mac-1, macrophage-1 antigen; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MBP, myelin basic protein; MMP, matrix metalloproteinase; MyD88, myeloid differentiation primary response 88; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor; NO, nitric oxide; Nrf2, nuclear factor erythroid 2–related factor 2; p-ERK, phosphorylated extracellular signal-regulated kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositide 3-kinase; p-JNK, phosphorylated c-Jun N-terminal kinase; PKC, protein kinase C; p-NR1, phosphorylated NMDA receptor subunit 1; p.o., per os; ROCK, Rho-associated protein kinase; ROS, reactive oxygen species; s.c., subcutaneous; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor alpha; TNFR1, tumor necrosis factor receptor 1; TrkA, tropomyosin receptor kinase A; TRPV1, transient receptor potential vanilloid type 1. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation; → denotes activation/stimulation/induction.

6.1.2. Terpenes and Terpenoids

Terpenes and terpenoids constitute an important class of plant secondary metabolites with anti-inflammatory, antioxidant, and neuromodulatory properties. Increasing evidence suggests that these compounds may attenuate neuropathic pain by modulating neuroimmune signaling, oxidative stress, glial activation, endocannabinoid pathways, and neuronal repair mechanisms [281]. Although most available data derive from experimental studies, findings across multiple neuropathic pain models indicate that terpenoids act on several molecular targets implicated in peripheral and central sensitization.

Among these compounds, β-caryophyllene is one of the most extensively studied and represents a promising terpenoid candidate for neuropathic pain modulation. This naturally occurring sesquiterpene functions as a selective cannabinoid receptor type 2 (CB₂) agonist and has demonstrated efficacy in DN, CIPN, and CCI models [100,101,234,240,282,283,284]. The primary activation of CB₂ receptors by β-caryophyllene initiates a signaling cascade that suppresses NF-κB and MAPK pathways. This upstream modulation subsequently leads to a secondary reduction in pro-inflammatory mediators (TNF-α, IL-1β, IL-6, and monocyte chemoattractant protein (MCP)-1 also referred to as CCL2) and the attenuation of glial activation. β-Caryophyllene also limits oxidative damage by reducing ROS generation and lipid peroxidation, and may suppress NLRP3 inflammasome activation through modulation of the AMPK/SIRT3/Nrf2 axis [240]. These findings suggest that β-caryophyllene acts at the intersection between inflammatory and redox pathways involved in neuropathic pain chronification.

Other terpenoids appear to exert complementary mechanisms. Limonene, a monoterpene abundant in citrus peels, promotes nerve regeneration and functional recovery after sciatic nerve injury while reducing neuroinflammation and nociceptive hypersensitivity [242,285,286]. Linalool, found in lavender and coriander, attenuates neuropathic pain by suppressing pro-inflammatory cytokine production and inhibiting ERK-dependent signaling pathways involved in central sensitization [287,288,289]. Notably, its efficacy is modality-specific; while it reduces mechanical and cold hypersensitivity, it has been reported to have no significant effect on thermal hyperalgesia in spinal nerve ligation models, suggesting a high degree of target specificity. Similarly, α-humulene and farnesol derivatives have shown anti-inflammatory and analgesic properties, partly through modulation of oxidative stress and intracellular signaling cascades associated with neuronal hyperexcitability [290,291].

Some terpenes may also interact with the endocannabinoid system through mechanisms distinct from CB₂ activation. Myrcene exerts antinociceptive effects through CB₁-dependent mechanisms, whereas farnesyl thiosalicylic acid attenuates neuropathic pain by inhibiting Ras/Raf/MEK/ERK signaling, a pathway involved in neuronal sensitization and inflammatory responses [292,293]. These observations support the mechanistic diversity of terpenoids and their capacity to target distinct but interconnected pathways involved in neuropathic pain.

Overall, terpenes and terpenoids appear to alleviate neuropathic pain through combined modulation of neuroinflammation, oxidative stress, glial reactivity, endocannabinoid signaling, and neuronal repair (Table 2). However, despite encouraging preclinical findings, clinical evidence is still lacking. Future studies should address pharmacokinetics, bioavailability, optimal dosing, formulation strategies, safety, and translational efficacy before these compounds can be considered evidence-based therapeutic options for neuropathic pain.

Table 2. Terpenoids with demonstrated effects in preclinical studies of neuropathic pain.

Nutraceutical	Source	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
β-Caryophyllene	Black pepper, cloves	DN	Male Swiss Webster and female BALB/c mice, male Sprague–Dawley rats, and human Schwann cells	9–27 µg (i.pl., in vivo), 10 and 30 mg/kg/day (i.p. or p.o., in vivo), and 75 µM (in vitro)	↓ Mechanical allodynia and thermal hyperalgesia via primary activation of CB2 receptors → ↓ MAPK/NF-κB signaling and a secondary reduction in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). In combination with cannabidiol: ↓ neuroinflammation via ↑ AMPK/SIRT3/Nrf2, ↓ NLRP3 inflammasome and NF-κB activation, ↓ oxidative stress, IL-1β, and IL-18; modulation of substance P.	[100,240,282]
		CCI	Male and female C57BL/6J and male CD1 mice	56–320 mg/kg/day (i.p) and 2.5 mg/kg/day (p.o., as part of the Noxiall® combination)	↓ Mechanical allodynia and thermal hyperalgesia; reversal of mechanical allodynia is mediated by CB2 receptor agonism, while thermal hyperalgesia reversal may involve additional receptor targets; BCP also reduces neuroinflammation by inhibiting immune cell activation.	[234,284]
		CIPN (Paclitaxel- and -oxaliplatin-induced)	Female and male Swiss mice	12.5–250 mg/kg/day (p.o.)	↓ Mechanical allodynia via CB2 receptor activation; modulation of TNF-α, IL-1β, IL-6, and IL-10; ↓ ROS production, lipid peroxidation, and 4-HNE adduct formation in the spinal cord; inhibition of p38 MAPK and NF-κB activation, and ↓ microglial activation (↓ Iba-1 immunoreactivity) and ↓ IL-1β expression. ↓ Cold allodynia via CB2-independent mechanisms, accompanied by attenuation of oxidative stress and neuroinflammation.	[101,283]
Limonene	Citrus peels	Sciatic nerve injury	Male Swiss mice	50 mg/kg/day (p.o.)	↑ Nerve regeneration and motor/sensory recovery; ↓ mechanical hyperalgesia via upstream ↑ pERK/ERK signaling and direct modulation of NGF/GAP-43 → ↓ secondary neuroinflammation (IL-1β, TNF-α) to promote regeneration.	[285]
Linalool	Lavender, coriander	Partial sciatic nerve ligation	Female Swiss mice	50 and 200 mg/kg/day (i.p.) (acute treatment) 50 mg/kg (chronic treatment, twice daily)	↓ Mechanical and cold hypersensitivity; ↓ peripheral inflammation (edema); and inhibition of nociceptive responses induced by spinal pro-inflammatory cytokines (IL-1β, TNF-α) and glutamate pathways.	[288]
		Spinal nerve ligation	Male C57/BL6 mice	100 mg/kg/day (s.c.)	↓ Mechanical allodynia (transiently) with repeated administration; no effect on thermal hyperalgesia; mechanism likely independent of PI3K/Akt signaling and modulation of spinal glial activation or IL-1β expression.	[287]
Myrcene	Mango, lemongrass, hops	CCI	Male and female C57BL/6J mice	1–200 mg/kg/day (i.p.)	↓ Mechanical allodynia via CB1-dependent antinociception (endocannabinoid system involvement; blocked by antagonists).	[292]
Farnesol and farnesol derivatives	Lemongrass, citronella	CCI	Male and female Wistar rats	2.5–10 μg (i.t.)	Farnesyl thiosalicylic acid: ↓ mechanical hyperalgesia, mechanical and cold allodynia via primary ↓ Ras/Raf/MEK/ERK2 signaling.	[293]

Abbreviations: AMPK, AMP-activated protein kinase; CB₁, cannabinoid receptor type 1; CB₂, cannabinoid receptor type 2; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; DN, diabetic neuropathy; ERK, extracellular signal-regulated kinase; GAP-43, growth-associated protein 43; GFAP, glial fibrillary acidic protein; HNE, hydroxynonenal protein; Iba-1, ionized calcium-binding adapter molecule 1; IL, Interleukin; i.p., intraperitoneal; i.pl., intraplantar; i.t., intrathecal; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MEK, MAPK/Erk kinase; NF-κB, nuclear factor kappa B; NGF, nerve growth factor; Nrf2, nuclear factor erythroid 2–related factor 2; p.o., per os; Raf, rapidly accelerated fibrosarcoma kinase; Ras, rat sarcoma; ROS, reactive oxygen species; s.c., subcutaneous; SIRT3, sirtuin 3; TNF-α, tumor necrosis factor alpha. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation; → denotes activation/stimulation/induction.

6.1.3. Alkaloids

Alkaloids are structurally diverse nitrogen-containing secondary metabolites that play important roles in plant defense and have long been utilized in medicine because of their broad pharmacological properties, including anesthetic, anti-inflammatory, cardioprotective, and analgesic activities [294]. Increasing evidence indicates that several plant-derived alkaloids can alleviate neuropathic pain by modulating nociceptive ion channels, neuroimmune signaling, oxidative stress, and neuronal plasticity. Compared with phytochemicals that primarily target inflammatory pathways, alkaloids often exhibit broader mechanistic diversity, acting at both peripheral and central levels of pain processing.

Capsaicin remains the most clinically established alkaloid-related compound for neuropathic pain treatment. This capsaicinoid and vanilloid alkaloid, derived from chili peppers, acts as a potent agonist of the TRPV1 channel, which is expressed on nociceptive neurons and immune cells involved in neuroinflammatory responses [295]. Although TRPV1 activation initially induces neuronal excitation, sustained stimulation results in a reversible defunctionalization of nociceptive terminals, characterized by calcium overload, neuropeptide depletion, and temporary loss of epidermal nerve fibers [295,296,297]. This localized reduction in peripheral nociceptive input contributes to analgesia.

Clinical studies indicate that high-concentration capsaicin patches can reduce pain in several neuropathic conditions, including painful DN, CIPN, spinal cord injury-associated neuropathic pain, and postherpetic neuralgia, while maintaining a favorable systemic safety profile [298,299,300]. Treatment has also been associated with increased intraepidermal nerve fiber density, GAP-43-positive nerve regeneration, improved sensory function, and reduced daily pain scores, suggesting that capsaicin may promote functional nerve remodeling rather than permanent denervation [300]. Similar findings have been reported in CCI models, where local capsaicin administration attenuated mechanical hyperalgesia, secondary hyperalgesia, and ongoing affective pain by selectively targeting hyperactive TRPV1-positive nociceptive terminals [301].

Beyond direct modulation of nociceptors, several alkaloids exert anti-neuropathic effects through regulation of intracellular signaling pathways involved in neuroinflammation. MAPK pathways, including ERK, JNK, and p38 MAPK, are central mediators of neuropathic pain because they regulate inflammatory gene transcription, glial activation, and neuronal sensitization [205,302]. Therefore, selective modulation of these pathways represents an important strategy for limiting chronic pain progression [303].

Isotalatizidine, a diterpenoid alkaloid isolated from Aconitum carmichaelii, appears to enhance endogenous analgesic mechanisms. In CCI models, intrathecal administration reduces mechanical allodynia in a dose-dependent manner through activation of the ERK1/2-cAMP response element-binding protein (CREB) signaling pathway in spinal microglia [304]. This pathway promotes the synthesis and release of dynorphin A, an endogenous opioid peptide that suppresses nociceptive transmission in the spinal cord. The analgesic effect is abolished by pharmacological inhibition of ERK1/2 or CREB, supporting the central role of this signaling cascade.

Berberine has demonstrated broad activity across traumatic nerve injury, DN, and CIPN models. Its effects appear to involve coordinated anti-inflammatory, antioxidant, and neuroregenerative mechanisms. In CIPN models, berberine primarily targets the TRPV1/NF-κB signaling axis in the DRG; this direct interaction subsequently reduces downstream NF-κB activation and MAPK phosphorylation, resulting in lower pro-inflammatory cytokine levels [305]. In sciatic nerve injury, berberine promotes functional recovery through inhibition of NLRP3 inflammasome activation and modulation of macrophage phenotypic responses, leading to reduced production of pro-inflammatory mediators and enhanced tissue repair, ultimately attenuating neuroinflammation and promoting structural nerve regeneration [306]. In DN, combined administration of berberine and tocopherol reduces NF-κB signaling, advanced glycation end-product accumulation, oxidative stress, and inflammatory cytokine production while restoring antioxidant defenses such as SOD and GSH [235].

Tetrandrine has shown efficacy in both traumatic and CIPN models through modulation of neuroimmune signaling. In oxaliplatin-induced neuropathy, tetrandrine reduces mechanical allodynia by regulating inflammation-related genes in the spinal cord, including suppression of Cxcl12 and enhancement of Nfkbia expression, resulting in reduced NF-κB activation and diminished immune-cell infiltration [307]. In spared nerve injury, tetrandrine attenuates mechanical hypersensitivity by suppressing microglial chemokine-like factor 1 (CKLF1) expression and disrupting a positive feedback loop involving NF-κB/IKK signaling. This reduces glial activation and pro-inflammatory cytokine production while increasing IL-10 expression, thereby restoring a more balanced spinal cytokine environment [308].

Collectively, alkaloids alleviate neuropathic pain through diverse yet convergent mechanisms including modulation of TRPV1-mediated nociceptive signaling, regulation of MAPK and NF-κB pathways, suppression of inflammasome activation, control of macrophage and microglial phenotypes, attenuation of oxidative stress, and enhancement of endogenous analgesic systems. Capsaicin has the strongest clinical support, whereas most other alkaloids remain supported mainly by preclinical evidence (Table 3). Further studies are needed to define optimal dosing, pharmacokinetic profiles, long-term safety, and translational efficacy.

Table 3. Alkaloids with demonstrated effects in experimental models and clinical conditions of neuropathic pain.

Nutraceutical	Source	Study Type	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
Capsaicin	Chili peppers	Clinical (Randomized, single-blind, crossover; 2 × 12 wk)	Spinal cord injury	11 subjects (5 highest dose and 6 lowest dose)	Single application of an 8% patch compared to a 0.025% patch control (topical)	↓ Refractory neuropathic pain (29–35%) and improves mobility without systemic side effects; it does not improve overall quality of life scores, as other health complications related to the injury likely overshadow the impact of pain relief.	[298]
		Clinical (Randomized for painful DN and open-label for non-painful DN; 3 mo)	Painful and non-painful DN	75 subjects (50 with painful DN and 25 with non-painful DN)	Single application of an 8% patch (topical)	↓ Average daily pain (NPRS); ↑ IENF density and GAP-43-positive subepidermal fibers (regeneration); improved warm perception thresholds and ↑ axon-reflex vasodilatation; TRPV1-mediated defunctionalization triggers reversible retraction followed by restoration of healthy nociceptive terminals.	[300]
		Preclinical	CCI	Adult male and female C57BL/6J mice	10 μg in 20 μL vehicle (s.c.)	↓ Mechanical and secondary hyperalgesia and ongoing affective pain: potent activation of TRPV1 channels triggers primary Ca2+ influx and calpain activation, which subsequently induces the reversible retraction of nociceptive terminals.	[301]
Isotalatizidine	Aconitum carmichaelii	Preclinical	CCI	Female C57BL/6 mice	0.1–1.0 mg/kg/day (i.t.)	↓ Mechanical allodynia (dose-dependent) via activation of the spinal microglial ERK1/2-CREB signaling axis, which triggers the expression and release of dynorphin A to inhibit pain transmission; effect is abolished by selective ERK or CREB inhibition.	[304]
Berberine	Berberis vulgaris, Coptis chinensis	Preclinical	CIPN (Cisplatin-induced)	Male C57BL/6 mice and	60–120 mg/kg/day (p.o., in vivo) and 10–30 μM (in vitro)	Primary ↓ DRG TRPV1/NF-κB axis → downstream suppression of injury-induced NF-κB activation and secondary cytokine production.	[305]
		Preclinical	Sciatic nerve injury	Male and female C57BL/6J	60–240 mg/kg/day (p.o.)	Dose-dependent ↑ motor and sensory recovery via macrophage NLRP3 inflammasome inhibition, modulating macrophage activation by reducing pro-inflammatory responses and enhancing reparative functions, thereby promoting nerve regeneration and reducing neuroinflammatory cytokine production.	[306]
		Preclinical	DN	Male Wistar rats	20 or 40 mg/kg berberine + 1000 mg/kg tocopherol (p.o.)	Synergistic tocopherol combination dose-dependently ↓ thermal and mechanical hyperalgesia via targeting hyperglycemia, oxidative stress, and neuroinflammation; ↓ NF-κB, TNF-α, and AGEs; ↑ SOD, GSH, and insulin; neuroprotection via ↓ NF-κB signaling and AGE accumulation, reducing metabolic neuropathy.	[235]
Tetrandrine	Stephania tetrandra	Preclinical	CIPN (Oxaliplatin-induced)	Male C57BL/6J mice	45 mg/kg/day (p.o.)	↓ Mechanical allodynia via upstream modulation of spinal inflammatory genes (↓ Cxcl12, ↑ Nfkbia) → ↓ primary NF-κB activation and ↓ CD4+ T-cell infiltration.	[307]
		Preclinical	Spared nerve injury	Male C57BL/6J mice	5–45 mg/kg/day (p.o.)	↓ Mechanical allodynia via spinal microglial CKLF1 downregulation, inhibiting NF-κB/IKK positive feedback, reducing TNF-α and IL-1β, suppressing glial activation, and increasing IL-10 to restore cytokine balance.	[308]

Abbreviations: AGE, advanced glycation end product; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; CKLF1, chemokine-like factor 1; CREB, cAMP response element-binding protein; Cxcl12, C-X-C motif chemokine ligand 12; DN, diabetic neuropathy; DRG, dorsal root ganglion; ERK, extracellular signal-regulated kinase; GAP43, growth-associated protein 43; GSH, glutathione; IENF, intraepidermal nerve fiber; IKK, IκB kinase; IL, interleukin; i.t., intrathecal; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; Nfkbia, NF-κB inhibitor alpha; NPRS, Numeric Pain Rating Scale; p.o., per os; s.c., subcutaneous; SOD, superoxide dismutase; TNF-α, tumor necrosis factor alpha; TRPV1, transient receptor potential vanilloid type 1; VEGFR-2, vascular endothelial growth factor receptor 2. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation; → denotes activation/stimulation/induction.

6.2. Fatty Acids and Lipid-Derived Nutraceuticals

Lipid-derived nutraceuticals, particularly polyunsaturated fatty acids (PUFAs), are relevant to neuropathic pain because of their roles in neuronal membrane integrity, inflammatory resolution, and neuroimmune regulation.

The omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily found in cold-water fish, are precursors of specialized pro-resolving mediators (SPMs), including resolvins, which contribute to the resolution of inflammation [309,310]. These lipid mediators exert their biological effects through specific G protein-coupled receptors, including ALX/FPR2, ChemR23 (also known as CMKLR1), and GPR32 (in humans), activating intracellular signaling pathways involving β-arrestin and PI3K/Akt. In neuropathic pain, these signaling cascades promote the resolution of neuroinflammation by limiting neutrophil infiltration, enhancing macrophage efferocytosis, attenuating maladaptive microglial activation, suppressing pro-inflammatory cytokine production, and restoring tissue homeostasis [310,311]. Through these anti-inflammatory and pro-resolving mechanisms, omega-3 fatty acids may influence neuropathic pain states characterized by persistent neuroinflammation. In preclinical models of chemotherapy-induced, traumatic, and constriction-induced neuropathy, EPA/DHA supplementation prevents or reverses mechanical and thermal hypersensitivity by reducing spinal and cerebral neuroinflammation, decreasing microglial activation and pro-inflammatory cytokine production, and promoting nerve regeneration and functional recovery [102,312,313]. Clinical evidence in DN suggests that daily omega-3 supplementation reduces sensory and affective pain scores, with effects associated with increased plasma DHA and correction of an altered omega-6/omega-3 ratio [314]. These findings support omega-3 fatty acids as pleiotropic nutritional modulators of neuroinflammatory and metabolic disturbances in neuropathic pain.

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that is also present in several food sources and has been investigated for pain of neuropathic and inflammatory origin [315]. PEA exerts its effects through primary activation of peroxisome proliferator-activated receptor-alpha (PPAR-α), which subsequently facilitates TRPV1 desensitization and modulates endocannabinoid signaling. These upstream events ultimately trigger the homeostatic resolution of neuroinflammation [316]. In animal models of CIPN and CCI, PEA alleviates hypersensitivity and promotes nerve regeneration through PPAR-α-dependent mechanisms, reducing neuroinflammation and preserving myelin structure [117,317]. In DN, oral PEA supplementation has been associated with reduced sensory pain, improved nerve conduction, and improvements in sleep and mood, potentially through suppression of systemic inflammation and modulation of mast cell activity [236,318,319].

Gamma-linolenic acid (GLA) is an omega-6 polyunsaturated fatty acid important for neural membrane structure and function [320]. In clinical studies of painful DN, GLA reduced pain intensity and total symptom scores, possibly by supporting membrane phospholipid composition, improving nerve conduction, and exerting antioxidative and vasodilatory effects [321]. Although these findings are encouraging, further studies are required to clarify its clinical relevance, optimal dose, and long-term efficacy.

Overall, lipid-derived nutraceuticals, including omega-3 fatty acids, PEA and GLA, may contribute to neuropathic pain management through complementary effects on neuroinflammation, membrane integrity, inflammatory resolution, and neuronal repair. Among these compounds, PEA and omega-3 fatty acids currently have comparatively stronger translational support, although larger controlled trials remain necessary (Table 4).

Table 4. Fatty acids and lipid-derived nutraceuticals with demonstrated effects in experimental models and clinical conditions of neuropathic pain.

Nutraceutical	Source	Study Type	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
Omega-3 (EPA/DHA)	Seafood (especially fatty fish), supplements and concentrated pharmaceutical preparations	Preclinical	CIPN (Paclitaxel- or oxaliplatin-induced)	Male C57BL/6 mice	2.3 g/kg containing 840 mg of ω-3 (460 mg EPA and 380 mg DHA) and 4 mg of tocopherol per 1 g (p.o., capsules)	↓ Mechanical and thermal hypersensitivity via ↓ spinal and cerebral neuroinflammation, microglial activation, and pro-inflammatory cytokines (TNF-α, IL-1β), with modulation of central BDNF and improved metabolic profile.	[312]
		Preclinical	Partial sciatic nerve ligation	Male and female Swiss mice	2.3 and 4.6 g/kg/day of commercial concentrate (Omacor®) containing 4.6% EPA and 3.6% DHA (p.o.)	↓ Mechanical and thermal hypersensitivity with ↑ functional nerve recovery via ↓ spinal neuroinflammation (↓ TNF production, MPO activity), ↑ structural regeneration, and modulation of nerve markers (GAP-43, ATF-3).	[102]
		Preclinical	CCI	Male Wistar rats	0.36 and 0.72 g/kg/day of concentrated salmon oil containing ~30% w/w omega-3 (17% EPA and 13% DHA) (p.o.)	↓ Thermal hyperalgesia and mechanical allodynia with ↑ functional recovery (SFI), ↑ axonal density and morphological regeneration, and protection against neuroma formation, which supports proper axonal regrowth and prevents associated spontaneous pain.	[313]
		Clinical (Single-arm pilot study; 3 mo)	DN	40 subjects (26 with NP symptoms)	1000 mg DHA and 200 mg EPA daily (oral, capsules)	Daily oral supplementation ↓ sensory and affective pain scores; these improvements correlated with ↑ plasma DHA and ↓ sphingosine levels, reflecting an improved omega-6/omega-3 balance and reduced lipotoxicity without altering clinical glycemic or lipid profiles.	[314]
PEA	Soy, chia, egg yolk, apples, lentils, black-eyed peas, potatoes, roasted coffee, human milk, among others	Preclinical	CIPN (Paclitaxel-induced)	Male CD1 mice	30 mg/kg/day (p.o.)	↓ Mechanical and thermal hypersensitivity via ↑ PPAR-α signaling, reducing spinal and hippocampal pro-inflammatory cytokines and restoring CB1 receptor expression.	[317]
		Preclinical	CCI	Male C57BL/6 mice	30 mg/kg/day (s.c.)	Prevented pain threshold alterations and ↑ nerve regeneration via PPAR-α; ↓ pro-inflammatory macrophage activation, edema, and COX-2; preserved myelin and axonal diameter.	[117]
		Clinical (Randomized placebo-controlled pilot and quadruple-blind or open-label clinical studies; 8 wk–6 mo)	DN	30–73 subjects with T1D/T2D diabetic neuropathy (painful neuropathy)	600 mg/day of micronized, bioavailable, or combined PEA formulations (oral, 300 mg; twice daily when specified)	Oral supplementation (alone or with ALA/SOD/vitamins) ↓ sensory pain and ↑ nerve function, sleep, and mood via ↓ IL-6/CRP, mast cell modulation, and restored PEA levels.	[236,318,319]
GLA	Evening primrose oil, borage oil	Clinical (Multicenter, randomized, double-blind, double-dummy, parallel-group, noninferiority trial; 12 wk)	DN	100 subjects (with T2D and painful DPN)	320 mg/day (taken orally as four 40 mg capsules twice daily)	↓ VAS and TSS scores, acting as a disease-modifying agent that restores neuronal membrane phospholipids and improves nerve conduction independently of glycemic control.	[321]

Abbreviations: ALA, alpha-lipoic acid; ATF-3, activating transcription factor 3; BDNF, brain-derived neurotrophic factor; CB₁, cannabinoid receptor type 1; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DHA, docosahexaenoic acid; DN, diabetic neuropathy; EPA, eicosapentaenoic acid; GAP-43, growth-associated protein 43; GLA, gamma-linolenic acid; IL, interleukin; MPO, myeloperoxidase; PEA, palmitoylethanolamide; p.o., per os; PPAR-α, peroxisome proliferator-activated receptor alpha; s.c., subcutaneous; SOD, superoxide dismutase; SFI, sciatic functional index; TNF, tumor necrosis factor; TSS, Total Symptom Scores; T1D, type 1 diabetes; T2D, type 2 diabetes; VAS, visual analogue scale. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation; → denotes activation/stimulation/induction.

6.3. Antioxidant Nutraceuticals with Anti-Inflammatory Actions

Oxidative stress is a central contributor to neuropathic pain pathogenesis, promoting neuronal injury, mitochondrial dysfunction, ion channel dysregulation, and amplification of neuroinflammatory signaling. Antioxidant nutraceuticals with anti-inflammatory properties may interrupt this cycle by directly reducing oxidative damage and indirectly suppressing redox-sensitive inflammatory pathways [322].

Alpha-lipoic acid (ALA) is a potent antioxidant that alleviates neuropathic pain through both direct and indirect mechanisms. Clinically, ALA reduces symptom scores and improves nerve function in DN, likely by mitigating hyperglycemia-induced oxidative stress and metabolic dysfunction [323,324]. In animal models of nerve injury and CIPN, ALA reverses hypersensitivity, improves nerve morphology, and restores motor function. The primary antioxidant activity of ALA directly reduces lipid peroxidation; this initial mitigation of oxidative stress triggers secondary homeostatic feedback, including the upregulation of endogenous defenses (SOD, GSH) and the downstream suppression of pro-inflammatory cytokines and glial activation, and inhibition of apoptotic pathways [325,326,327].

Coenzyme Q10 (CoQ10), an endogenous lipid-soluble antioxidant and essential component of the mitochondrial electron transport chain, has therapeutic potential across neuropathic pain conditions by targeting mitochondrial dysfunction and oxidative stress. In DN, adjunct CoQ10 supplementation reduces pain intensity and increases responder rates [328]. In diabetic rodent models, CoQ10 prevents sensory deficits, restores nerve conduction, and protects DRG neurons [103]. In vitro, it protects human motor neurons from chemotherapy-induced toxicity by reducing ROS generation and preserving mitochondrial membrane potential [104]. In nerve injury models, CoQ10 increases pain thresholds, reduces spinal neuronal loss, and promotes structural regeneration by counteracting oxidative damage and supporting mitochondrial bioenergetics [105,106,107].

Resveratrol also shows broad efficacy in preclinical models of neuropathic pain through antioxidant, anti-inflammatory, mitochondrial, neuroprotective, epigenetic, and autophagy-related mechanisms. It promotes nerve regeneration after injury and alleviates pain-related behaviors in CIPN, DN, spinal cord injury, and CCI models. Mechanistically, resveratrol modulates VEGF, COX-2, TRPV channels, JAK/STAT signaling, cytokine production, and mitochondrial dynamics. In addition, it acts as a SIRT1 activator, promoting histone and transcription factor deacetylation and thereby regulating the expression of inflammatory and oxidative stress-related genes through epigenetic mechanisms [108,109,110,118,329,330,331,332,333,334,335,336]. In CCI models, resveratrol has been associated with restoration of mitochondrial fission–fusion balance, including reduced Drp1 expression and increased OPA1 expression, together with improved antioxidant defenses such as increased SOD activity [334]. By limiting excessive mitochondrial fragmentation and supporting mitochondrial network integrity, resveratrol may reduce mitochondrial ROS production, preserve mitochondrial membrane potential, decrease mitochondrial danger-signal release, and indirectly attenuate NLRP3 inflammasome activation [151,154,159,160,161,162,334]. These effects may be further reinforced through activation of the AMPK/SIRT1 signaling axis, which promotes autophagy and mitochondrial quality control, thereby limiting ROS accumulation, suppressing NLRP3 inflammasome activation, and reducing neuroinflammation [212,334]. Collectively, these findings suggest that resveratrol acts upstream of both oxidative stress and neuroinflammation by preserving mitochondrial homeostasis rather than functioning solely as a direct antioxidant, highlighting its potential as a nutraceutical for neuropathic pain management.

Acetyl-L-carnitine (ALC), found in red meat and dairy products, has shown clinical benefits in DN. In patients, ALC improves neuropathy symptom and disability scores, enhances nerve conduction, reduces pain intensity, and improves vibration perception [337,338,339,340]. Preclinically, ALC alleviates thermal pain and protects nerve structure by reducing demyelination, axonal atrophy, and mitochondrial swelling in Schwann cells [341].

Sulforaphane, derived from cruciferous vegetables, has demonstrated analgesic and neuroprotective effects in preclinical neuropathic pain models. In CCI, it reduces mechanical and thermal hypersensitivity by suppressing pro-inflammatory mediators, enhancing anti-inflammatory signaling, activating Nrf2/HO-1 pathways, and reducing microglial activation and MAPK phosphorylation [111,342]. In DN, sulforaphane improves sensory function through antioxidant and anti-inflammatory mechanisms involving activation of Nrf2 and inhibition of NF-κB signaling [119].

Collectively, antioxidant nutraceuticals may attenuate neuropathic pain by restoring redox homeostasis, improving mitochondrial function, suppressing neuroinflammation, and supporting neuronal survival (Table 5). However, the level of clinical evidence varies considerably among compounds, with stronger support for ALA and ALC than for resveratrol, sulforaphane, or CoQ10 in neuropathic pain.

Table 5. Antioxidant nutraceuticals with demonstrated effects in experimental models and clinical conditions of neuropathic pain.

Nutraceutical	Source	Study Type	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
ALA	Spinach, peas, broccoli sprouts, and tomatoes	Clinical (Randomized, double-blind, placebo-controlled studies (4–5 wk); one multicenter trial)	DN	100–181 patients with T1D/T2D and symptomatic diabetic polyneuropathy	600–1800 mg/day (oral)	Oral administration may ↓ TSS and improve neuropathic deficits, though clinical results vary across studies; primary antioxidant activity directly ↓ hyperglycemia-driven oxidative stress → secondary homeostatic feedback that improves metabolic and neurological deficits, although improvements in nerve conduction and H-reflex were not significantly demonstrated in these short-term trials.	[323,324]
		Preclinical	CCI	Male Sprague–Dawley and Wistar rats	25–50 mg/kg/day (i.p.)	Reversed pain threshold deficits and ↑ nerve morphology via SOD/CAT↑, ↓ p53 apoptosis, and ↓ SGC expansion; ↓ thermal hyperalgesia and cold allodynia with ↑ motor coordination via GSH restoration and ↓ MDA/NO, reducing axonal degeneration and maintaining neuroprotection.	[325,326]
		Preclinical	CIPN (Paclitaxel-induced)	Male Sprague–Dawley rats	15–60 mg/kg/day (i.p.)	↑ Mechanical thresholds and ↓ cold via compartment-specific immunomodulation (spinal cord and DRG); treatment inhibits the IL-17 inflammatory axis (↓ IL-17, TNF-α, HSP-90α, MMP-13) and modulates AGE–RAGE/apoptotic pathways, effectively blocking the neuroinflammation-injury cascade even at low doses.	[327]
CoQ10	Meat, fish, nuts	Clinical(Single-site, randomized, double-blind, placebo-controlled, parallel-group trial; 8 wk)	DN	112 subjects (T2D and painful DN)	300 mg/day (oral, capsules of 100 mg three times daily)	Oral supplementation as adjunct to pregabalin ↓ pain intensity (NRS scores) and ↑ the responder rate (≥50% pain reduction); it also significantly improved sleep-interference scores and led to higher rates of global clinical improvement (CGIC/PGIC) through its antioxidant and anti-inflammatory properties.	[328]
		Preclinical	DN	Male and female C57BL/KsJm mice	1 g/kg (oral, dietary supplementation via food pellets)	↓ Tactile/thermal hypoalgesia and NCV impairment; ↓ L5 DRG neuronal loss via Bax/p-Akt modulation and PLCβ3 preservation.	[103]
		Preclinical	CIPN (5-Fluorouracil + methotrexate + paclitaxel + doxorubicin + vincristine)	Human iPSC-derived motor neuron progenitors	10 µM	Protected iPSC-derived motor neurons from chemotoxicity (including paclitaxel and vincristine) by increasing viability, reducing ROS generation, and preserving mitochondrial membrane potential under oxidative stress.	[104]
		Preclinical	CCI	Male Wistar rats	10–200 mg/kg/day (i.p. or p.o.)	↑ Pain thresholds (mechanical/thermal) and ↓ dorsal horn neuronal loss via mitochondrial stabilization and ↓ permeability transition pore opening. It further ↓ hypersensitivity by reducing ROS-induced oxidative damage and ↑ functional recovery (SFI) by increasing the number of myelinated axons and preserving myelin/axonal structure following both short- and long-term nerve injury.	[105,106,107]
Resveratrol	Grapes, berries	Preclinical	Sciatic nerve injury	Male Sprague–Dawley rats and PC-12 cells	50–200 mg/kg/day (i.p., in vivo) and 25 µM (in vitro)	↑ Nerve regeneration and rapid motor repair (SFI/toe-spreading) via p300-mediated VEGF signaling; treatment increases p-Akt/Akt and p-p300/p300 ratios, facilitating axonal elongation and protecting ventral spinal motor neurons.	[108]
		Preclinical	CIPN (Oxaliplatin- and paclitaxel-induced)	Male Sprague–Dawley rats	1–200 mg/kg (i.t. or i.p.)	Relieves OXA-induced allodynia by inhibiting spinal COX-2/ROS neuroinflammation (GFAP, cytokines, NF-κB); prevents PTX-induced neuropathy by blocking DRG TRPV1 upregulation and ERK phosphorylation.	[109,329]
		Preclinical	Partial sciatic nerve ligation	Male Sprague–Dawley rats	100–200 mg/kg (i.p.)	↓ Mechanical/thermal hypersensitivity via ↓ DRG P2X3 upregulation and ERK phosphorylation.	[330]
		Preclinical	Spinal cord injury	Male Sprague–Dawley rats	300 µg in a volume of 10 µL (i.t.)	↓ Mechanical allodynia via ↓ spinal JAK2/STAT3 signaling and neuroinflammation, with ↓ TNF-α, IL-1β, and IL-6 in the lumbar dorsal horn.	[331]
		Preclinical	DN	Male and female C57BL/6j mice	25 mg/kg/day (i.p.)	↓ TRPV4 current density and Ca2+ influx in DRG neurons; ↓ oxidative stress (mtSOX/ROS) and caspase-3/8/9-mediated apoptosis; restores GSH and vitamin E levels across neural and peripheral tissues.	[110]
		Preclinical	CCI	Male Sprague–Dawley rats, female Balb-c and male C57BL/6 mice	30–300 μg (i.t.) or 5–400 mg/kg (i.p. or p.o.); administered once daily or as a single oral dose.	Multi-target neuropathic pain relief: ↓ sensory deficits via Sirt1–miR-182–Nav1.7 axis and epigenetic H3 deacetylation; ↓ neuroinflammation by balancing cytokines (↓ IL-6/↑ IL-10) and enhancing spinal IL-4R signaling; restores mitochondrial homeostasis (↓ DRP1/↑ OPA1, ↑ SOD); and alleviates trigeminal neuralgia via AMPK-mediated MAPK inhibition.	[118,332,333,334,335,336]
ALC	Red meats and dairy products	Clinical (Randomized clinical trials, predominantly multicenter, double-blind, placebo- or active-controlled (phase II and prospective studies); up to 52 wk)	DN	59–1257 subjects	100 mg/day (i.m.) for 10 d followed by 2000 mg/day (oral); 1500–4800 mg/day (oral, capsules)	↓ NSS/NDS scores and ↑ vibration perception; ↓ VAS/PI-NRS pain via nerve regeneration (confirmed by sural biopsy showing ↑ myelinated fibers); improves SNCV/amplitude (long-term); synergistic combinations with methylcobalamin and ALA provide superior clinical outcomes.	[337,338,339,340]
		Preclinical	DN	Male Kunming mice	125 mg/kg/day (p.o.)	Alleviates DPN by restoring tail-flick latency (↓ thermal hyperalgesia) and improving nerve ultrastructure (↓ Schwann cell mitochondrial swelling, demyelination, and axonal atrophy); effects are mediated by ↑ local and circulatory IGF-1 levels.	[341]
Sulforaphane	Cruciferous vegetables (broccoli sprouts)	Preclinical	CCI	Male C57BL/6J mice	0.1–100 mg/kg/day (i.p.)	Dose-dependently alleviates NP by suppressing neuroinflammation (↓ TNF-α, IL-1β, IL-6, COX-2, iNOS; ↑IL-10) and oxidative stress (via Nrf2/HO-1 activation). It further reduces microglial activation and MAPK phosphorylation (JNK/ERK/p38) while upregulating μ-opioid receptors to enhance endogenous and exogenous analgesia.	[111,342]
		Preclinical	DN	Male Sprague–Dawley rats	0.5 and 1 mg/kg/day (i.p.)	Counteracted sensory deficits via ↑ Nrf2 and ↓ NF-κB signaling, with ↓ TNF-α, IL-1β, and IL-6.	[119]

Abbreviations: AGE-RAGE, advanced glycation end products–receptor for advanced glycation end products; ALA, alpha-lipoic acid; ALC, acetyl-L-carnitine; AMPK, AMP-activated protein kinase; CAT, catalase; CCI, chronic constriction injury; CGIC, clinician global impression of change; CGRP, calcitonin gene-related peptide; CIPN, chemotherapy-induced peripheral neuropathy; CoQ10, coenzyme Q10; COX-2, cyclooxygenase-2; DN, diabetic neuropathy; DRG, dorsal root ganglion; DRP1, dynamin-related protein 1; ERK, extracellular signal-regulated kinase; GFAP, glial fibrillary acidic protein; GSH, glutathione; H reflex, Hoffmann reflex; HSP-90α, heat shock protein 90 alpha; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; IL-1R2, interleukin-1 receptor type 2; IL-4Rα, interleukin-4 receptor alpha; i.m., intramuscular; iNOS, inducible nitric oxide synthase; i.p., intraperitoneal; iPSC, induced pluripotent stem cell; i.t., intrathecal; JAK, janus kinase 2; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MMP-13, matrix metalloproteinase-13; mtSOX, mitochondrial superoxide; Nav1.7, voltage-gated sodium channel 1.7; NCV, nerve conduction velocity; NDS, Neurological Disability Score; NF-κB, nuclear factor kappa B; NO, nitric oxide; Nrf2, nuclear factor erythroid 2–related factor 2; NRS, Numeric Rating Scale; NSS, Neurological Symptom Score; OPA1, optic atrophy 1; OXA, oxaliplatin; p.o., per os; P2X3, purinergic receptor P2X ligand-gated ion channel 3; PGIC, patient global impression of change; PI-NRS, Pain Intensity Numeric Rating Scale; PLCβ3, phospholipase C beta 3; PTX, paclitaxel; ROS, reactive oxygen species; SGC, satellite glial cell; SFI, Sciatic Functional Index; Sirt1, sirtuin 1; SNCV, sural nerve conduction velocity; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3; TNF-α, tumor necrosis factor alpha; TRPV, transient receptor potential vanilloid; TSS, Total Symptom Scores; VAS, visual analogue scale; VEGF, vascular endothelial growth factor. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation.

6.4. Vitamins and Micronutrients

Vitamins and micronutrients are essential dietary components involved in neuronal function, metabolic homeostasis, myelin synthesis, antioxidant defense, and immune regulation [99]. Deficiencies or imbalances in specific vitamins and trace elements may contribute to the development or progression of neuropathic pain, particularly in conditions characterized by metabolic dysfunction, impaired nerve repair, oxidative stress, and chronic neuroinflammation [31]. Through regulation of redox homeostasis, neuroimmune responses, neuronal excitability, and regenerative processes, these nutrients have emerged as complementary candidates for neuropathic pain prevention and management [343].

B-complex vitamins, obtained from whole grains, meat, and legumes, have been investigated in neuropathic pain, particularly in DN. In clinical studies, combinations containing methylcobalamin have reduced pain intensity and improved nerve function, including nerve conduction velocity [237]. Preclinical evidence indicates that neurotropic B vitamins, especially vitamins B1, B6, and B12, alleviate allodynia and hyperalgesia, support nerve regeneration, reduce neuronal hyperexcitability, and improve functional recovery in several nerve injury models [238,344,345,346,347,348,349,350,351]. Synergistic effects have also been reported among B vitamins and when combined with other agents, suggesting that these compounds may enhance endogenous repair mechanisms and modulate nociceptive processing through complementary pathways. However, target specificity is also evident in combination therapies; for instance, while low-dose B-vitamins show synergy with carbamazepine for thermal hyperalgesia, the combination of vitamin B6 and carbamazepine resulted in no synergy for mechanical thresholds [352,353,354].

Vitamin D, beyond its classical role in calcium homeostasis, has also been implicated in neuropathic pain modulation. Clinical studies associate low vitamin D levels with worse symptoms in DN, spinal cord injury, and CIPN, potentially through increased inflammation, reduced neurotrophic support, oxidative stress, and altered nociceptive signaling [355,356,357]. Mechanistically, vitamin D exerts genomic effects through binding to the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor (RXR) to regulate the transcription of genes involved in neuronal survival, neurotrophic support, antioxidant defenses, and immune homeostasis, including BDNF and NGF. In addition, vitamin D may exert rapid non-genomic actions through membrane-associated receptors, such as protein disulfide isomerase family A member 3 (PDIA3), modulating intracellular calcium signaling and neuronal excitability [358,359]. In preclinical nerve injury models, vitamin D supplementation reduced pain-related behaviors, improved functional recovery, and exerted antioxidant, anti-inflammatory, neurotrophic, and anti-ferroptotic effects [360,361,362].

Vitamin E has also been investigated in neuropathic pain because of its antioxidant and membrane-stabilizing properties. Clinical studies addressing vitamin E supplementation in patients with DN suggest improvements in sensory and motor nerve conduction velocity, indicating possible effects on myelin preservation or remyelination, rather than direct axonal regeneration [363,364,365,366]. In CIPN, vitamin E supplementation has been associated with reduced symptoms in some studies; however, findings remain inconsistent. While early Phase II trials were promising, larger Phase III trials and oxaliplatin-specific studies have failed to show a significant benefit in preventing or mitigating neurotoxicity, highlighting a substantial translational gap [367,368,369,370,371,372,373,374,375]. Preclinical models suggest that vitamin E may reverse mechanical allodynia by reducing spinal oxidative stress, decreasing NMDA receptor phosphorylation, and attenuating central sensitization, while also protecting axonal and myelin integrity [376,377].

Magnesium contributes to antinociception primarily through antagonism of NMDA receptors, thereby limiting central sensitization and reducing established pain hypersensitivity [378]. Low magnesium levels may impair nerve conduction and contribute to DN-related pain alterations [379]. Clinical and preclinical studies report that magnesium improves neuropathic symptoms and reduces thermal and tactile allodynia, mainly through spinal NMDA receptor blockade and reduction in oxidative stress [380,381,382]. Magnesium also suppresses pain behaviors in CCI and may reduce neurotoxicity in CIPN by stabilizing neuronal excitability and counteracting calcium and magnesium disturbances associated with oxaliplatin metabolism [383,384,385,386]. It is important to note that the efficacy of magnesium is model-dependent; in CCI models, while it reduces heat hyperalgesia, it has no significant effect on mechanical hyperalgesia or ectopic discharges. Additionally, clinical evidence for preventing acute cold-induced symptoms in CIPN remains conflicting.

Zinc, an essential trace element involved in antioxidant defense, immune regulation, and ion channel modulation, has also been investigated in neuropathic pain. Clinical data in DN indicate that low zinc levels correlate with greater symptom severity and impaired nerve conduction [387]. Preclinical studies in diabetic models show that zinc supplementation attenuates nerve conduction deficits and tactile allodynia by reducing oxidative stress and upregulating antioxidant defenses [388]. In CIPN, zinc reduces mechanical hypersensitivity through a TRPV1-dependent mechanism that involves intracellular modulation of TRPV1 activity and participation of specific zinc transporters for its analgesic effect [389].

Overall, vitamins and micronutrients may help modulate neuropathic pain by supporting neuronal metabolism, myelin integrity, antioxidant defenses, neuroinflammatory regulation, ion channel function, and nerve repair (Table 6). B-complex vitamins, vitamins D and E, magnesium, and zinc show the strongest mechanistic rationale, with varying levels of preclinical and clinical evidence. Their effectiveness likely depends on factors such as nutritional status, pain etiology, dose, formulation, treatment duration, and concomitant therapies. Therefore, these nutrients should be considered supportive, mechanism-based interventions rather than universal analgesics, particularly for patients with deficiencies or increased metabolic, oxidative, or inflammatory burden. Further well-designed clinical trials are needed to define their role in integrative neuropathic pain management.

Table 6. Vitamins and micronutrients with demonstrated effects in experimental models and clinical conditions of neuropathic pain.

Nutraceutical	Source	Study Type	Condition	Model	Doses/Concentrations (Administration Route)	Main Effects and Proposed Mechanisms	References
B-complex vitamins	Whole grains, meat, legumes	Clinical (Open-label, randomized, controlled, parallel-group pilot study; 12 wk)	DN	30 subjects with T2D and peripheral neuropathy	Pregabalin 75 mg + methylcobalamin 750 µg + ALA 100 mg twice daily vs. pregabalin 75 mg twice daily (oral, tablets)	Methylcobalamin + ALA + pregabalin ↓ NRS pain and sleep interference, and ↑ common peroneal NCV.	[237]
		Preclinical	DN	Male Wistar and male and female Sprague–Dawley rats	Methylcobalamin: 500 μg/kg/day (i.m.); vitamin B cocktail (B1/B6/B12): 20–180/20–180/0.2–1.8 mg/kg (s.c.); benfotiamine: 100 mg/kg or thiamine nitrate: 70.18 mg/kg (p.o.)	Prevented AGE formation and nerve damage in early experimental diabetes; ↑ igf-1 expression; and dose-dependently ↓ tactile allodynia and formalin hyperalgesia with ↑ sensory NCV.	[344,345,352]
		Preclinical	CCI	Male Sprague–Dawley rats	66 mg/kg (i.p., in vivo) and 0.1–10 mM (in vitro)	↓ Thermal hyperalgesia, neuronal hyperexcitability, and sodium current alterations in injured DRG neurons.	[346]
		Preclinical	Peripheral nerve injury	Female Wistar and male AO rats and male ICR mice	Vitamin B12: 1 mg/kg/day (i.p.) + vitamin D3: 3500 IU/kg/week (p.o.); commercial vitamin B-complex (Beviplex): 1.85 mL/kg/day (i.p.); mecobalamin: 65–130 μg/kg/day (i.p.)	↑ Nerve healing and functional recovery (SFI) by upregulating GAP43 and neurotrophic factors (NGF, BDNF, CNTF), thickening myelin, and preventing muscle atrophy. Mechanistically, they resolve neuroinflammation by inducing CaV1.2-mediated modulation of macrophage activation, reducing pro-inflammatory mediators (↓ TNF-α, ↓ iNOS) while increasing anti-inflammatory and tissue repair-associated mediators (↑ IL-4, ↑ IL-10).	[238,347,353]
		Preclinical	Sciatic nerve injury	Adult male and female Wistar rats and P9 cells	Methylcobalamin: 1 mg/kg/day (s.c., in vivo) or 1 nM–100 μM (in vitro); vitamin B12: 2 mg/kg (local injection) or 2 mg/kg/day (i.p.) ± dexamethasone (1 mg/kg) or ALA (2 mg/kg/day)	↑ Axonal regeneration and nerve recovery with ↓ edema, myelin degeneration, and neuronal apoptosis; +dexamethasone ↑ peripheral nerve repair and BDNF; ↑ neurite outgrowth and survival via ERK/Akt activation.	[348,349,350,351]
		Preclinical	Trigeminal pain	Male Wistar rats	Vitamin B1/B6/B12: 18/18/1.8 or 180/180/18 mg/kg/day (s.c.); carbamazepine: 10 or 30 mg/kg (i.p.)	Repeated B1/B6/B12 ↓ heat hyperalgesia; B12 selectively ↓ cold and B6 selectively ↓ mechanical hyperalgesia. Low-dose B-vitamins + Carbamazepine → synergistic ↑ thermal (heat/cold) antihyperalgesia. Note: B6 + CBZ → no synergy for mechanical thresholds.	[354]
Vitamin D	fatty fish, eggs, milk, and certain mushrooms	Clinical (Cross-sectional study)	DN	59 subjects (17 painful DN, 14 painless-DN, 14 no-DN, and 14 healthy volunteers)	Serum 25-hydroxyvitamin D [25(OH)D] concentrations (no intervention)	↓ Vitamin D levels correlate with ↓ cold detection thresholds and ↓ subepidermal nerve fiber density, implicating small-fiber neuropathy affecting nociceptors.	[355]
		Clinical (Cross-sectional study)	Spinal cord injury	182 subjects (96 with NP and 86 without NP)	Serum 25-hydroxyvitamin D [25(OH)D] concentrations (no intervention)	↓ Vitamin D → pro-inflammatory state (↑ TNF-α, IFN-γ). Deficiency modulates ↓ neurotrophic factors (BDNF, NT-3) and dysregulates TRPV1 channels.	[356]
		Clinical (Prospective cohort study)	CIPN (Paclitaxel-induced)	300 women with stage I-III breast cancer	Serum 25-hydroxyvitamin D [25(OH)D] concentrations (no intervention)	↓ Vitamin D levels → ↑ risk (7-fold) of severe sensory CIPN and ↓ time to symptom onset (8.2 vs 10.4 weeks). Mechanistically, it regulates NGF synthesis, modulates inflammatory cytokines, ↓ oxidative stress, and promotes myelin repair in peripheral nerves.	[357]
		Preclinical	CCI	Male Wistar and Sprague–Dawley rats	450–500 IU/kg/day (p.o.)	↓ Mechanical/thermal hypersensitivity and ↑ SFI via spinal antioxidant effects (↓ SAG, H2O2; ↑ GSH/total thiols, TAC). Treatment ↓ hyperalgesia/allodynia and ↑ recovery via cerebral opioid signaling modulation (↑ Pomc, ↓ Pdyn/Penk). Genomic effects are mediated through Erk1/2, Map2k1/2, Pth, and Src pathways.	[360,361]
		Preclinical	Spared nerve injury	Male Sprague–Dawley rats	0.5–2 μg (i.t.)	Dose-dependently ↓ mechanical allodynia and preserved spinal GABAergic interneurons via VDR-mediated ↓ PKCα/NOX4 signaling. This inhibits mitochondria-associated ferroptosis/dysfunction and restores key regulators GPX4, SLC7A11, GSH, and SOD.	[362]
Vitamin E	Nuts, seeds, vegetable oils	Clinical (Randomized clinical studies, including two phase II double-blind RCTs and two prospective controlled studies; 8 wk–12 mo)	DN	80–100 subjects with T2DM or diabetic peripheral neuropathy	400 mg/day (oral, capsules)	↑ NCV (velocity only) in sural, median, and tibial nerves, suggesting myelin repair/protection. Mechanistically, this correlates with ↑ serum NGF rather than changes in inflammatory or oxidative biomarkers. Clinically, significantly ↓ neuropathic pain (VAS, NPS, BPI) and ↑ quality of life. Note: NCV improvements are transient and diminish after 6 months of treatment washout.	[363,364,365,366]
		Clinical (Randomized clinical trials (phase II/III and controlled studies)	CIPN (Cisplatin-, paclitaxel-, and oxaliplatin-induced)	27–189 subjects receiving neurotoxic chemotherapy	300–600 mg/day (oral, capsules, soft gels, tablets, or E-Vigel®) administered during chemotherapy and continued for up to 3 months after treatment	Several RCTs demonstrated beneficial effects of vitamin E in cisplatin- and paclitaxel-induced CIPN, including reduced incidence of neuropathy and lower PNP/TNS scores. In contrast, larger phase III trials in oxaliplatin-induced CIPN failed to demonstrate significant efficacy in preventing or reducing neurotoxicity.	[367,368,369,370,371,372,373,374,375]
		Preclinical	Spinal nerve ligation	Male Sprague–Dawley rats	Vitamin E (DL-α-tocopherol acetate): 0.1–5 g/kg (i.p., single dose) or 50–100 mg/kg/day for 7 d; 3–50 mg (i.t.)	Reversed mechanical allodynia via desensitization of spinal WDR neurons; ↓ ROS → ↓ pNR1 expression, attenuating central sensitization.	[376]
		Preclinical	Sciatic nerve injury	Male Wistar rats	Vitamin E: 100–200 mg/kg (i.p.) and pregabalin: 1–30 mg/kg (i.p.)	Vitamin E (±pregabalin) → neuroprotection via partial reversal of axonal/myelin degeneration and normalization of Schwann cell counts in the ligated nerve. Low-dose combination effectively reversed Wallerian degeneration and inflammatory responses to levels similar to sham groups. Note: vitamin E did not affect locomotor activity.	[377]
Magnesium	Leafy greens, nuts, seeds	Clinical (Randomized, double-blind, placebo-controlled clinical trial; 8 wk)	DN	60 subjects with T2D and confirmed peripheral neuropathy	Magnesium citrate: 300 mg (oral, sachet)	Sustained improvement in NDS scores over 2 months (↓ 1.27 vs 0.30 in control). This demonstrates neuroprotection via ↓ nerve damage, ↓ inflammation, and ↓ oxidative stress, potentially slowing the progression of DN.	[380]
		Preclinical	DN	Male Sprague–Dawley and Wistar rats	Magnesium sulfate: 296 mg/L or 10 g/L (oral, drinking water)	↓ Thermal/tactile allodynia and delayed mechanical hypersensitivity. ↓ Spinal pNR1 expression restores the voltage-dependent NMDA receptor blockade, attenuating central sensitization. Mg provides NMDA inhibitory, antioxidant, and (model-dependent) normoglycemic effects.	[381,382]
		Preclinical	CCI	Male Sprague–Dawley rats	Magnesium sulfate: 600 mg/kg (s.c.); 185–750 μg (i.t.); 750–7000 μg (perineural)	↓ Heat hyperalgesia and mechanical allodynia via spinal NMDA receptor modulation, with magnesium enhancing voltage-dependent channel block. Note: no effect on mechano-hyperalgesia or ectopic discharges.	[383]
		Clinical (Randomized clinical trials, including placebo-controlled trial, phase III double-blind placebo-controlled trial, and phase III randomized study)	CIPN (Oxaliplatin-induced)	102–732 subjects with colorectal cancer receiving oxaliplatin-based chemotherapy	Calcium gluconate (1 g) + magnesium sulfate (1 g) or calcium glubionate (2.25 mmol) + magnesium chloride (4 mmol) (i.v. infusion, before and after oxaliplatin)	↓ Cumulative/chronic neurotoxicity and ↓ neuromuscular symptoms (spasms, trismus). Counteracts oxalate-mediated Ca2+/Mg2+ chelation, stabilizing voltage-gated Na+ channels. Note: Conflicting evidence for acute cold-induced symptoms. No impact on chemotherapy efficacy observed.	[384,385,386]
Zinc	Meat, shellfish, legumes	Clinical (Case–control cross-sectional study)	DN	120 subjects (40 DN, 40 non-DN, and 40 healthy controls)	Endogenous serum zinc measured via direct colorimetric test	↓ Zinc levels correlate with ↑ neuropathy severity (NSC, MNSI) and impaired electrophysiological function, with ↓ conduction velocity and amplitudes in motor and sensory nerves.	[387]
		Preclinical	DN	Male Sprague–Dawley rats	5 mg/kg/day (i.p.)	Attenuates the decline of MNCV and ↑ tactile threshold, effectively mitigating allodynia. ↑ MT1 expression and ↓ PARP-1 levels, leading to ↓ oxidative stress (reduced MDA) in the sciatic nerve.	[388]
		Preclinical	CIPN (Paclitaxel-induced)	Male and female C57BL/6J mice	3–30 mM in a volume of 10 μL (i.pl.)	Dose-dependently ↓ mechanical hypersensitivity. Analgesia is mediated by intracellular inhibition of TRPV1 (IC50 ~15 nM). Dual-entry routes identified: acute inhibition requires TRPA1-mediated zinc influx, whereas relief of chronic pain requires ZIP3, ZIP6, and ZIP7 transporters. Note: single injection provides sustained relief for >4 days.	[389]

Abbreviations: ALA, alpha-lipoic acid; BDNF, brain-derived neurotrophic factor; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; D3, vitamin D3; DN, diabetic neuropathy; DRG, dorsal root ganglion; ERK, extracellular signal-regulated kinase; GABA, gamma-aminobutyric acid; GPX4, glutathione peroxidase; GSH, glutathione; IFN-γ, interferon gamma; IGF1, insulin-like growth factor 1; i.m., intramuscular; i.p., intraperitoneal; i.pl., intraplantar; i.t., intrathecal; i.v., intravenous; Map2k1/2, mitogen-activated protein kinase 1 and 2; MDA, malondialdehyde; MNCV, motor nerve conduction velocity; MNSI, Michigan Neuropathy Screening Instrument; MT1, metallothionein 1; NCV, nerve conduction velocity; NDS, Neurological Disability Score; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NOX4, NADPH oxidase 4; NRS, Numeric Rating Scale; NSC, Neuropathy Symptom Count; NT-3, neurotrophin-3; Penk, proenkephalin; Pdyn, prodynorphin; PKCα, protein kinase C alpha; pNR1, phosphorylated NMDA receptor subunit 1; Pomc, proopiomelanocortin; Pth, parathyroid hormone; ROS, reactive oxygen species; SAG, S-adenosylhomocysteine; s.c., subcutaneous; SFI, Sciatic Functional Index; SLC7A11, solute carrier family 7 member 11; SOD, superoxide dismutase; Src, proto-oncogene tyrosine-protein kinase Src; TAC, total antioxidant capacity; TNS, Total Neuropathy Score; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid type 1; T2D, type 2 diabetes; VDR, vitamin D receptor; WDR, wide dynamic range; ZIP, Zrt-/Irt-like protein. Symbols: ↑ denotes upregulation/increase/improvement; ↓ denotes downregulation/decrease/attenuation; → denotes activation/stimulation/induction.

7. Conclusions and Future Perspectives

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology, chronic nature, and limited responsiveness to currently available pharmacological therapies. Increasing evidence indicates that neuroinflammation and oxidative stress are central and interconnected mechanisms driving the initiation and maintenance of neuropathic pain. The reciprocal amplification between inflammatory signaling pathways and redox imbalance contributes to neuronal dysfunction, peripheral and central sensitization, and the persistence of pain. Consequently, therapeutic strategies capable of simultaneously targeting these processes have emerged as attractive alternatives to conventional symptom-oriented treatments.

In this context, nutraceuticals have gained considerable attention owing to their ability to modulate multiple molecular pathways involved in neuropathic pain. A wide range of dietary bioactive compounds, including flavonoids, terpenoids, alkaloids, polyunsaturated fatty acids, antioxidant molecules, vitamins, and micronutrients, have demonstrated beneficial effects in experimental models of neuropathic pain. These compounds exert pleiotropic actions through the regulation of neuroinflammatory mediators, attenuation of oxidative stress, enhancement of endogenous antioxidant defenses, modulation of glial cell activity, restoration of neuronal homeostasis, and, for selected compounds, through epigenetic regulation and preservation of mitochondrial homeostasis via autophagy-related pathways. As a result, nutraceuticals may attenuate pain hypersensitivity while, depending on the compound and experimental context, also promoting nerve regeneration and functional recovery through additional neuroprotective and reparative mechanisms. These outcomes represent related but distinct biological processes and should not be considered interchangeable. Importantly, several nutraceuticals, such as omega-3 fatty acids, ALA, PEA, vitamin D, and B-complex vitamins, have also shown encouraging results in clinical settings, suggesting their potential utility as complementary therapeutic approaches.

Despite these promising findings, the current body of evidence presents several important limitations. Most mechanistic data originate from preclinical studies conducted in animal models, which may not fully reproduce the complexity and heterogeneity of human neuropathic pain conditions. Moreover, important interspecies differences in neuroimmune signaling—including differences in microglial transcriptional programs and the expression of purinergic, chemokine, and other immune-related receptors—may influence the translational relevance of mechanisms identified in rodent models. Clinical studies remain relatively limited in number and often suffer from small sample sizes, with most trials enrolling fewer than 100 participants, short intervention periods, heterogeneous patient populations, and variations in outcome measures. Furthermore, differences in nutraceutical composition, extraction methods, formulation strategies, bioavailability, and dosing regimens complicate comparisons across studies and hinder the establishment of clear clinical recommendations. The available evidence is also varying according to the experimental model, treatment protocol, and outcome evaluated, highlighting the importance of interpreting preclinical findings within their specific biological context. These limitations underscore the need for cautious interpretation of existing data and highlight the gap between experimental efficacy and clinical translation.

A major challenge for the field is the lack of standardized nutraceutical formulations and harmonized methodological approaches. Future investigations should prioritize the development of well-characterized products with defined chemical composition, quality control standards, optimized bioavailability, and rigorous characterization of dose–response relationships to identify therapeutic windows and avoid potential hormetic effects. In parallel, large-scale, randomized, placebo-controlled clinical trials are required to establish efficacy, determine optimal dosing strategies, evaluate long-term safety, and identify patient populations most likely to benefit from specific interventions. The incorporation of standardized pain assessment tools, objective biomarkers of neuroinflammation and oxidative stress, and clinically meaningful outcome measures will be essential for improving study comparability and strengthening the evidence base. Future studies should also integrate human-relevant experimental models and translational biomarkers to improve the prediction of clinical efficacy and facilitate the validation of mechanisms identified in preclinical studies. Addressing these challenges also requires a balanced assessment of target specificity and therapeutic efficacy. The recognition of inconsistent or negative findings—where specific compounds fail to affect certain pain modalities or do not reproduce encouraging preclinical results in clinical settings—is essential for refining mechanism-based therapeutic strategies and improving the translational value of future research.

In conclusion, nutraceuticals represent a promising class of multi-target interventions capable of modulating key mechanisms underlying neuropathic pain, particularly neuroinflammation and oxidative stress. While current evidence supports their potential as complementary therapeutic strategies, robust clinical validation remains necessary before widespread implementation in routine clinical practice. Continued interdisciplinary research integrating mechanistic, translational, and clinical perspectives will be crucial to fully realize the therapeutic potential of nutraceuticals in the prevention and management of neuropathic pain.