Clinical studies have demonstrated that chronic pain elevates the risk of memory impairments and is associated with multidimensional deficits across cognitive domains (Innes and Sambamoorthi, 2020). Cognitive dysfunction is significantly more prevalent in chronic pain patients than in healthy populations, affecting attention, executive function, and learning and memory. Among these, learning and memory functions appear particularly susceptible to chronic pain, with pain persistence correlating with accelerated memory decline (Higgins et al., 2018).

Patients with fibromyalgia and osteoarthritis, two common subtypes of chronic pain, perform worse on delayed recall and working memory tasks compared to healthy controls (Apkarian et al., 2011). Meta-analyses further reveal small to moderate deficits in long-term memory among fibromyalgia patients relative to healthy adults (Bell et al., 2018). Persistent moderate to severe pain exhibits a dose–response relationship with subsequent memory decline (Rong et al., 2021). Pain subtypes also demonstrate domain-specific cognitive associations: osteoarthritis primarily affects visuospatial and executive functions, whereas fibromyalgia predominantly impairs working memory (Tiara and Fidiana, 2021). The severity and duration of pain are key determinants of cognitive outcomes. Patients with moderate to severe joint pain face a higher risk of memory decline than those with mild pain, and each additional year of pain duration is associated with progressive reductions in episodic memory scores (van der Leeuw et al., 2018; Horgas et al., 2022). Longitudinal studies indicate that individuals with persistent pain exceeding 6 months have a substantially increased risk of developing major memory impairments over a 10-year period, independent of confounding factors such as age and education (Whitlock et al., 2017). Collectively, these findings indicate that chronic pain significantly impairs learning and long-term memory, with pain intensity, subtype, and duration serving as critical factors informing clinical intervention strategies.

Multiple clinical studies have confirmed a robust association between chronic pain and attentional dysfunction. Chronic pain impairs various aspects of attention, including sustained, selective, and divided attention (Bell et al., 2018). Acute experimentally induced pain and chronic pain affect attention differently: acute pain primarily reduces accuracy in n-back and attention-switching tasks, whereas chronic pain patients exhibit deficits in divided attention tasks (Moore et al., 2019). Evidence indicates that chronic pain disrupts performance on attention-demanding tasks (Higgins et al., 2018) and alters brain activity associated with attentional processing (Pinheiro et al., 2016). Clinically, many patients report difficulties concentrating, with some experiencing persistent attention deficits (Legrain et al., 2009). Impairments in attention may underlie the overall mild cognitive impairment observed in chronic pain populations (Ferreira et al., 2016). Prospective studies show that patients with knee osteoarthritis experience declines in short-term memory and attention, with the effects being more pronounced in those with chronic pain (Wen et al., 2024). In specific domains, such as selective and sustained attention, task performance efficiency is generally lower in chronic pain patients compared to healthy controls (Arévalo-Martínez et al., 2024). Chronic pain also impairs internal attention, thereby hindering creative thinking, and significantly reduces performance in attention-demanding tasks (Richards et al., 2018; Gubler et al., 2022). Collectively, these findings suggest that chronic pain exacerbates cognitive load by disrupting core attentional processes, such as information filtering, sustained focus, and multitasking, ultimately contributing to broader cognitive decline.

Cognitive flexibility, a critical component of executive function, is primarily mediated by the prefrontal cortex (PFC; Cowen et al., 2018). Accumulating evidence indicates that patients with chronic pain often exhibit mild to moderate impairments in executive function, with deficits in this domain being particularly pronounced (Berryman et al., 2014). In individuals with MCI, both executive function and memory are compromised, suggesting that pain may accelerate cognitive decline in this vulnerable population (Lautenbacher et al., 2021). Adolescents suffering from chronic musculoskeletal pain also show poorer executive function compared with age- and sex-matched healthy controls (Jastrowski Mano et al., 2020). Moreover, chronic pain patients receiving long-term opioid therapy demonstrate significant deficits in cognitive flexibility, highlighting the combined impact of pain and pharmacological treatment on executive function (Schiltenwolf et al., 2014). Notably, the duration of pain emerges as the strongest predictor of cognitive decline, with longer-lasting pain correlating with more severe impairments in cognitive flexibility (Jongsma et al., 2011; Cowen et al., 2018). Although overall cognitive dysfunction in chronic pain is generally mild, deficits in specific domains such as executive function are more prominent relative to healthy individuals (Richards et al., 2018; Arévalo-Martínez et al., 2024). These observations are consistent with findings in chronic low back pain, where impairments in executive function and working memory have also been reported (Baker et al., 2018; Richards et al., 2018; Corti et al., 2021). Collectively, current evidence suggests a mild to moderate association between chronic pain and executive function, underscoring the need for further studies to elucidate underlying mechanisms and develop targeted intervention strategies, including neuroimaging investigations.

Chronic pain is frequently associated with deficits in working memory, a core component of short-term memory, as well as other cognitive domains. The bidirectional relationship between pain and working memory impairment has been well documented (Higgins et al., 2018; Procento et al., 2021). Clinical studies consistently show that, compared with pain-free individuals, patients with chronic pain not only perform worse on working memory tasks but also report greater subjective deficits (Mazza et al., 2018; Rader et al., 2025). Longitudinal research in older adults indicates that persistent pain interference correlates with declines in overall cognitive function, particularly in immediate and delayed memory (Bell T. et al., 2022). Similarly, Ling et al. (2007) reported significant impairments in prospective memory among patients with chronic back pain relative to controls. Chronic low back pain and fibromyalgia patients also exhibit lower performance on working memory and short-term memory assessments compared with healthy populations (Bell et al., 2018; Corti et al., 2021) Disease-specific analyses reveal that individuals with hip osteoarthritis show notable reductions in short-term memory on neuropsychological testing (Kazim et al., 2023). Moreover, chronic pain patients undergoing long-term opioid therapy demonstrate even greater working memory impairments, suggesting that pharmacological factors may exacerbate cognitive deficits (Schiltenwolf et al., 2014). Collectively, these findings indicate that chronic pain exerts a substantial negative impact on short-term memory function.

Cognitive dysfunction in chronic pain patients is reflected in standardized tests as slower reaction times and reduced information processing efficiency. Among cognitive domains, processing speed appears particularly vulnerable to the effects of pain, often more so than memory or reasoning (Bell T. R. et al., 2022). Studies demonstrate that, relative to healthy controls, individuals with chronic pain exhibit significant deficits in basic cognitive tasks, including visual attention, graph processing speed, visual scanning, and number sequencing (Schiltenwolf et al., 2014). Their information processing speed and mental flexibility are also markedly impaired (Ferreira et al., 2016). Prospective epidemiological evidence indicates that declines in processing speed among chronic pain patients occur independently of confounding factors such as age and education (Rouch et al., 2021). Cross-sectional analyses across different pain subtypes support these findings: patients with chronic low back pain show significant impairments in processing speed (Corti et al., 2021), whereas individuals with fibromyalgia demonstrate reduced information processing efficiency compared to healthy populations (Serrano et al., 2022). Community-dwelling older adults with chronic musculoskeletal pain similarly exhibit delayed processing speed (Murata et al., 2017). Cognitive deficits in chronic pain are often accompanied by impairments in delayed memory, problem-solving abilities, and altered psychological states. Importantly, effective interventions targeting pain can partially restore information processing efficiency and overall cognitive function, likely by reducing central nervous system (CNS) overload (Abd-Elsayed and Gyorfi, 2023). Collectively, current clinical evidence consistently supports the association between chronic pain and declines in neurocognitive performance, with core impairments predominantly involving processing speed, attention, and memory. These findings provide a theoretical basis for implementing cognitive-protective strategies in pain management.

Across neuropathic pain models, hippocampal dysfunction emerges as the most consistent neuropathological feature, with structural alterations such as reduced dendritic complexity and spine density, as well as synaptic plasticity impairments including deficits in long-term potentiation (LTP; Wang et al., 2021; Hisaoka-Nakashima et al., 2022b; Hisaoka-Nakashima et al., 2022a; Jiang et al., 2024). Neuroinflammation is another recurring feature, characterized by microglial and astrocytic activation, elevated proinflammatory cytokines (e.g., IL-6, TNF-α), and subsequent neuronal apoptosis (Palazzo et al., 2016; Cui et al., 2020). Epigenetic modifications, such as histone deacetylase overexpression and global DNA hypomethylation, along with neurotransmitter receptor changes (e.g., NMDA receptor subunit imbalance, GABAAR-α5 upregulation), further contribute to cognitive deficits (Jang et al., 2021; Cai et al., 2022). Notably, chronic constriction injury (CCI) and spared nerve injury (SNI) models in APP/PS1 transgenic mice replicate both pain-induced memory impairment and amyloid pathology (Gong et al., 2017; Chen L. et al., 2023), offering unique value for studying the comorbidity of chronic pain and neurodegenerative disease.

Common rodent models, including CCI, SNI, spinal nerve ligation (SNL), partial sciatic nerve ligation (PSNL), and complete Freund’s adjuvant (CFA) induction—have consistently demonstrated significant cognitive impairment following neuropathic pain (Palazzo et al., 2016; Wang et al., 2021; Hisaoka-Nakashima et al., 2022b; Hisaoka-Nakashima et al., 2022a). Most studies have focused on spatial learning, memory, and attention. In Morris water maze (MWM) testing, SNI, SNL, and CCI animals exhibit clear spatial learning and memory deficits (Du et al., 2021; Hua et al., 2022; Chen L. et al., 2023). CCI mice show persistent pain and cognitive decline 21–28 days post-surgery in both MWM and fear conditioning tests (FCT; Zhang Y. et al., 2023), along with reduced spontaneous alternation rates in Y-maze and lower novel object recognition (NOR) performance at 14–21 days (Zheng et al., 2023; Zhu et al., 2024). Similarly, SNI rats spend less time exploring novel objects in NOR tests, and SNI mice show reduced alternation behavior and impaired object recognition within 1 month, with partial recovery after 12 months (Guida et al., 2022; Liu et al., 2024). PSNL models induce progressive deficits from 2 weeks to 6 months, affecting both alternation rates and NOR indices (Jang et al., 2021; Hisaoka-Nakashima et al., 2022b; Hisaoka-Nakashima et al., 2022a). Long-term, working, and short-term memory impairments are frequent across species (Phelps et al., 2021b; Phelps et al., 2021a; Cai et al., 2022; Xu et al., 2024), though some studies report no detectable changes within the first week (Zhang X. et al., 2023), suggesting that cognitive impairment is closely linked to the chronicity of nociceptive processing.

Sex hormones exert profound modulatory effects on both nociception and cognition, providing a plausible mechanistic basis for the sex differences observed in chronic pain–related cognitive deficits. Estrogen, in particular, enhances hippocampal-dependent learning and memory by promoting dendritic spine formation, facilitating long-term potentiation (LTP), and modulating glutamatergic and cholinergic signaling (Ebner et al., 2015; Hara et al., 2015). It also exerts potent anti-inflammatory effects in the central nervous system (CNS), attenuating microglial activation and downregulating proinflammatory cytokines such as TNF-α and IL-1β (Liu et al., 2017; Fiore and Austin, 2018). These actions may protect female animals from hippocampal and prefrontal cortical dysfunction during chronic pain states. Progesterone similarly supports cognitive resilience by promoting myelin repair, enhancing GABAergic inhibition, and regulating neurosteroid synthesis, thereby reducing excitotoxicity (Kummer et al., 2020).

In contrast, testosterone has been shown to influence both pain sensitivity and cognitive performance in males, with declining levels associated with increased neuroinflammation, impaired synaptic plasticity, and deficits in spatial memory (Shansky et al., 2010; Han et al., 2024b). Androgen receptors in the hippocampus and prefrontal cortex regulate gene expression related to neurogenesis, axonal growth, and dopaminergic signaling, which may underlie the male-specific vulnerability to chronic pain–induced memory impairment (Cardoso-Cruz et al., 2019a). Moreover, fluctuations in sex hormone levels, such as those occurring across the estrous cycle, menopause, or andropause, can dynamically alter the neural substrates of pain and cognition, contributing to temporal variability in symptom severity (Cardoso-Cruz et al., 2022).

At the molecular level, sex hormones modulate epigenetic landscapes in pain- and cognition-related brain regions. Estrogen receptor activation can induce histone acetylation at promoters of synaptic plasticity genes, while testosterone depletion has been linked to increased DNA methylation of genes involved in neurotrophic signaling (Journée et al., 2023). These epigenetic effects may partly explain the persistence or reversibility of cognitive deficits in chronic pain conditions. Taken together, hormonal modulation represents a critical axis for understanding sex-specific cognitive outcomes in chronic pain, and future preclinical studies should incorporate hormone profiling and receptor-targeted interventions to better translate findings to clinical populations.

Despite substantial progress, limitations remain. Different pain models yield heterogeneous cognitive outcomes, limiting cross-study comparability. Moreover, research has predominantly targeted spatial and working memory, with less emphasis on executive function, sustained attention, and other clinically relevant domains. Moving forward, comprehensive behavioral batteries and multimodal assessment strategies are essential to capture the full cognitive spectrum of chronic pain in preclinical settings and to bridge the translational gap between animal models and human pathology.

Chronic pain may consume substantial cognitive resources, thereby reducing the capacity to perform complex cognitive tasks (Phelps et al., 2021b; Phelps et al., 2021a). Neurobiologically pain-related cognitive dysfunction is associated with structural and functional remodeling of distributed brain networks, with core pathological changes occurring in the hippocampus, PFC, and anterior cingulate cortex (ACC).

The hippocampus, critical for memory encoding and consolidation, exhibits impaired synaptic plasticity and heightened neuroinflammatory responses in neuropathic pain models. Reduced neurogenesis in the dentate gyrus (DG) is directly linked to short-term and recognition memory impairments (Kodama et al., 2011; Ren et al., 2011), alongside abnormalities in long-term potentiation (LTP; Kodama et al., 2007). Elevated hippocampal levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and MCP-1 exacerbate neuroinflammation, further impairing cognition (Liu et al., 2017; Fiore and Austin, 2018). Following sciatic nerve injury, increased acetylated α-tubulin suggests that altered microtubule stability may disrupt synaptic plasticity and contribute to learning and memory deficits (You et al., 2018). Chronic inflammatory pain also induces selective hippocampal-independent memory deficits via neuroinflammation and synaptic loss (Yang et al., 2014). Rather than directly mediating nociception, the hippocampus may modulate pain-related behaviors indirectly through cognitive resource allocation (Xu et al., 2024).

The PFC, particularly the mPFC is central to executive functions, decision-making, and attention. Neural injury can inactivate the mPFC via glutamatergic synaptic inhibition, leading to decision-making deficits (Ji et al., 2010; Kummer et al., 2020). Disruption of the mPFC–dorsal hippocampus CA1 (mPFC–dCA1) circuit impairs memory (Han et al., 2024a), while optogenetic inhibition of glutamatergic neurons in the prelimbic cortex (PL)-mPFC pathway reverses neuropathic pain–related working memory deficits by restoring mPFC–dCA1 synchrony and local firing activity (Cardoso-Cruz et al., 2019b). The PL-mPFC exerts its influence partly through direct excitatory projections to the nucleus accumbens (NAcc) core and indirect modulation via interconnected neurons (Domingo-Rodriguez et al., 2020). Selective inhibition of PL-mPFC terminals projecting to the NAcc partially rescues spatial working memory deficits and modifies PFC–striatal connectivity without affecting nociceptive sensitivity (Cardoso-Cruz et al., 2022). These findings suggest that chronic pain disrupts PFC network integration, leading to impairments in recognition and spatial memory.

The ACC, a limbic structure integral to cognition, learning, memory, and decision-making, exhibits neuronal hyperactivity in chronic pain, characterized by increased spontaneous firing and an imbalance between excitatory and inhibitory signaling (Cardoso-Cruz et al., 2022). High-frequency stimulation of the ACC enhances pyramidal neuron activity, indicating that an excitatory/inhibitory (E/I) imbalance may reinforce maladaptive pain-related memory consolidation (Cardoso-Cruz et al., 2022; Zhu et al., 2022). Restoring oligodendrocyte myelination in the ACC can normalize network activity and alleviate cognitive impairments (Hasan et al., 2023). These findings underscore the need for detailed mapping of ACC subcircuits and their maladaptive plasticity during chronic pain.

Chronic pain–induced cognitive dysfunction arises from multi-regional interactions involving inflammatory mediator dysregulation (Wang et al., 2021), glutamate–GABA imbalance (Zhu et al., 2022), and synaptic plasticity abnormalities (Zhang X. et al., 2023). Persistent nociceptive input disrupts the E/I balance within the mPFC and ACC, impairing their normal processing capacity (Qi et al., 2022; Song et al., 2024). Amygdala-driven mPFC dysfunction plays a key role in pain-related cognitive impairments (Ji et al., 2010). Chronic visceral pain, for instance, disrupts theta oscillatory synchrony between the basolateral amygdala (BLA) and ACC, leading to executive deficits in visceral hypersensitive rats (Cao et al., 2016). Neuropathic pain reduces the excitability and synaptic efficiency of dorsal CA1 pyramidal neurons, decreasing glutamatergic input to the mPFC and thereby exacerbating pain sensitivity and cognitive decline (Han et al., 2024b). Additionally, the periaqueductal gray (PAG), a central hub for descending pain modulation, receives cortical inputs mainly from the anterior dorsal raphe (DR) and mPFC (Ong et al., 2019); dysfunction in the PAG–DR circuit may also contribute to cognitive impairments (Deng et al., 2023). These pain-induced behavioral changes are related to structural and functional alterations in multiple brain regions (May, 2008). Collectively, structural and functional alterations within the hippocampus, PFC, ACC, and interconnected regions form the neural substrate for chronic pain–associated cognitive dysfunction. The interplay between these regions, mediated by maladaptive neuroinflammation, disrupted synaptic signaling, and network-level dysregulation, offers multiple potential targets for therapeutic intervention.

Cellular damage within the CNS constitutes a key pathological substrate underlying chronic pain–associated cognitive dysfunction. Pain-related activation of neurons and glial cells in the PFC and hippocampus promotes abnormal release of pro-inflammatory mediators, disrupts synaptic plasticity, and contributes to behavioral deficits (Mohammadi et al., 2020; Yao et al., 2024). Central to this process is the phenotypic transformation of glial cells, particularly the polarization of microglia toward the pro-inflammatory M1 phenotype and the transformation of astrocytes into the neurotoxic A1 subtype. These changes disrupt neuron–glia homeostasis and exacerbate cognitive decline.

Commonly prescribed analgesics for chronic pain exhibit bidirectional effects on cognitive function. Agents such as gabapentin, opioids, and N-methyl-D-aspartate receptor (NMDAR) antagonists have been reported to impair domains including memory, executive function, and attention (Shem et al., 2018; Pask et al., 2020). The cognitive impact of opioids remains controversial: while some studies indicate potential cognitive improvement in patients with conditions such as low back pain (Jamison et al., 2003; Tassain et al., 2003), the preponderance of evidence associates chronic opioid therapy with measurable cognitive deficits in this population (Kurita et al., 2015; Richards et al., 2018). Specifically, morphine administration has been shown to induce transient anterograde and retrograde memory impairments (Kamboj et al., 2005), although no consistent correlation has been established between cognitive decline and opioid dosage or treatment duration (Sjøgren et al., 2005). Similarly, repeated exposure to NMDAR antagonists such as ketamine can lead to spatial memory deficits, likely linked to reduced activation of the hippocampus and parahippocampal gyrus (Morgan et al., 2014). While short-term analgesia or relief from pain-related stress may indirectly enhance cognitive performance (Wolrich et al., 2014; Ferreira et al., 2016), prolonged use of these agents tends to exacerbate cognitive impairment risk. To address this issue, future investigations should systematically characterize the dose–response relationship by considering the type of medication, its dosage, and treatment duration. Such analyses are essential to clarify the causal association between analgesic therapy and cognitive performance in chronic pain patients.

Emerging therapeutic strategies for chronic pain-associated cognitive dysfunction increasingly emphasize multi-target approaches. Pharmacological interventions targeting neuroinflammation and neurotrophic regulation have shown promising preclinical efficacy. For instance, infliximab can reverse neuroinflammation and restore hippocampal neurogenesis, thereby improving cognitive function (Yao et al., 2024). Curcumin and its nanoformulations attenuate neuropathic pain and memory deficits by reducing hippocampal IL-1β and TNF-α levels and repairing synaptic ultrastructure (Zhang et al., 2018; Du et al., 2021). Similarly, flurbiprofen ester and oral magnesium levetiracetam inhibit neuroinflammatory responses, alleviating both neuropathic pain and associated cognitive impairments (Zhou X. et al., 2021; Huang et al., 2022). Modulation of the glutamatergic system represents another therapeutic avenue. The NMDA receptor agonist d-aspartate restores glutamate transmission and improves cognitive deficits (Palazzo et al., 2016), whereas the NMDA receptor antagonist memantine protects spatial memory by preventing postoperative hippocampal LTP impairment (Morel et al., 2013). Additionally, chloramphenicol promotes myelin regeneration, mitigating CCI-induced reductions in neuronal activity and enhancing memory function (Zhu et al., 2024). Synaptamide has also been shown to reverse dendritic spine loss and restore LTP, thereby improving working memory (Tyrtyshnaia et al., 2021). Epigenetic regulation offers further potential. The methyl donor S-adenosylmethionine (SAM) preserves DNA methylation in the prefrontal cortex, alleviating cognitive decline (Grégoire et al., 2017), while SCFAs enhance synaptic transmission through histone acetylation. Preclinical evidence also supports the neuroprotective effects of anti-TNF-α, anti-IL-1β, anti-IL-6 agents, and endocannabinoid-like compounds (Lowe et al., 2021; Ortí-Casañ et al., 2022). Despite these advances, clinical translation remains challenging due to limitations in pharmacodynamic stability, blood–brain barrier permeability, and long-term safety. Future research should integrate multi-omics approaches with cross-scale neuroimaging to develop combination therapies that simultaneously target neuroinflammation, synaptic plasticity, and epigenetic modulation, ultimately achieving both pain alleviation and cognitive protection.

Acupuncture has emerged as a promising non-pharmacological strategy for alleviating chronic pain and associated cognitive deficits following peripheral nerve injury, demonstrating multi-target regulatory potential. Preclinical studies indicate that acupuncture can restore epigenetic homeostasis by modulating DNA methylation in the PFC. Specifically, it reverses chronic pain-induced methylation abnormalities of genes such as Nr4a1 and Rasgrp1, and normalizes global DNA methylation patterns in the PFC, periaqueductal gray, hippocampus, and amygdala (Jang et al., 2021). Electroacupuncture has been shown to enhance cognitive function via synergistic mechanisms. Four weeks of continuous treatment significantly increase mechanical pain thresholds, and hippocampal proteomic analyses have identified molecular correlates underlying improvements in neuropathic pain-associated cognitive deficits (Jang et al., 2019; Gong et al., 2021).

Collectively, these findings suggest that acupuncture can modulate the “pain–neuroinflammation–cognitive impairment” axis through dual mechanisms: epigenetic regulation and synaptic functional remodeling. This evidence highlights acupuncture as a novel, multi-target, non-pharmacological intervention for managing chronic pain comorbidities. A summary of preclinical research on therapeutic interventions is provided in Table 4.