Cognitive Behavioral Therapy and Pain Chronification: Neuroimmune Rationale, Evidence Boundaries, and Trial Design Priorities: A Structured Narrative Review

Abstract

Background

Pain chronification is a dynamic transition in which persistent pain may be shaped by interacting nociceptive, peripheral, spinal, supraspinal, neuroimmune, endocrine and cognitive-affective processes. Cognitive Behavioral Therapy (CBT) has clinical value in chronic pain, but claims about glial modulation and disease modification require careful qualification.

Objective

To evaluate CBT as an early, mechanism-informed and hypothesis-generating intervention while distinguishing clinical efficacy, neuroimmune plausibility, prevention hypotheses and disease-modifying claims.

Methods

We conducted a structured narrative review using prespecified evidence domains. PubMed/MEDLINE searches covering January 2014 to September 10, 2026 were complemented by citation chasing and selected landmark mechanistic articles. Sources were organized by evidence domain, study type and interpretive role, including pain chronification, neuroimmune and glial mechanisms, brain-network mechanisms, CBT outcomes, psychoneuroimmune pathways, perioperative prevention hypotheses, risk phenotyping and scalable delivery. No quantitative pooling or formal systematic/scoping-review workflow was performed.

Results

Experimental and translational studies support neuroimmune contributions to central sensitization and pain maintenance, whereas human evidence for direct CBT effects on microglial or astrocytic activation remains insufficient. CBT produces reproducible, generally small effects on pain intensity and more consistent benefits for interference, disability, distress, coping, sleep and function.

Conclusion

CBT should be presented as a clinically valuable component of multimodal care and as a testable psychoneuroimmune hypothesis, not as a proven preventive, glial-targeting or disease-modifying treatment. Risk-stratified, early, component-specific and mechanism-embedded trials are needed before prevention claims are made.

Introduction

Chronic pain is better conceived as an active transition rather than pain that simply persists after 3 months. Nociception refers to neural encoding of noxious stimuli, whereas pain is a sensory and emotional experience. Tissue injury may generate nociceptive input that resolves with repair, yet pain may persist in some patients as nociceptive input interacts with peripheral and central sensitisation, immune signalling, descending modulation, affective learning, sleep disruption and behavioural adaptation.^1–4 This transition-based framing has clinical importance because it defines a period in which risk processes for persistent pain may still be measurable and modifiable.

This framing also explains the relevance of Cognitive Behavioral Therapy (CBT) to pain biology without making CBT a direct biological treatment. CBT focuses on threat appraisal, catastrophizing, avoidance, inactivity, insomnia, emotional distress and maladaptive coping. These processes can influence attention, prediction, autonomic arousal, sleep quality and engagement with rehabilitation, and are therefore plausible upstream modifiers of pain trajectories.^5–8

The issue at hand is not whether CBT has clinical significance but the degree to which its effects on pain and function can be mechanistically explained. Microglia, astrocytes, chemokines and BDNF-TrkB signaling may contribute to pain-related processing in specific experimental and translational contexts.^9,10 Clinical CBT trials address outcomes such as interference, distress, coping and function,⁵ whereas psychoneuroimmunology studies of peripheral markers address a different, indirect question.¹¹ These lines of evidence are therefore supportive of plausibility but do not prove that CBT suppresses human glial activity directly.

Despite substantial literature, three gaps remain: evidence from clinical CBT trials, experimental glial studies and peripheral biomarker research is often treated as one causal chain; direct human evidence that CBT alters central glial activity is lacking; and early CBT has not been shown to prevent persistent pain. These gaps motivate the structured narrative synthesis and mechanism-embedded trial agenda developed here.^5,9–11

The thesis is therefore testable but deliberately bounded: CBT could influence the risk or course of persistent pain through specified psychological and behavioral mediators, including threat appraisal, sleep, avoidance and stress physiology, with possible downstream immune changes.^{3,4,6–8,11–15} The framework is intended primarily for acute-to-persistent trajectories such as chronic postsurgical pain and other high-risk transition contexts; it is not presented as a universal mechanism shared by all chronic pain conditions. Future studies should specify CBT components, risk phenotypes, mediator timing and biological endpoints. Figure 1 summarizes this organizing framework and its interpretive constraints.

Figure 1.

Psychoneuroimmune framework of Cognitive Behavioral Therapy (CBT) in pain chronification. The radial schematic is an organizing model for six connected domains: acute-to-persistent pain transition, neuroimmune activation, central sensitization and glial signaling, brain-network and cognitive-affective amplification, CBT-modifiable mediators, and evidence boundaries with trial-design priorities. It is intended primarily for acute-to-persistent trajectories such as chronic postsurgical pain and analogous high-risk contexts, not as a universal causal map for all chronic pain conditions. Nociceptive input, immune, glial, neural-network, cognitive-affective and behavioral processes are shown as interacting domains; arrows indicate proposed relationships rather than uniformly established human causality. Threat appraisal, catastrophizing, sleep regulation, autonomic tone, hypothalamic-pituitary-adrenal (HPA)-axis activity, inflammatory tone, function and self-efficacy are candidate CBT-modifiable mediators. The evidence-boundary domain distinguishes established clinical advantages in function and interference from possible stress-sleep-immune modulation and the unproven assertion that CBT directly inhibits human glial activation. Future trials should be risk-stratified, early, longitudinal and mechanism-embedded; repeated mediator assessment, immune biomarkers and neuroimaging endpoints should be treated as mechanistic probes rather than surrogate measures of glial modulation. In the figure, the green check mark denotes an established clinical benefit; the yellow question mark denotes plausible but indirect stress-sleep-immune modulation; the red cross denotes unproven direct glial suppression by CBT; bold labels identify domain headings and evidence-status categories; blue arrows indicate proposed relationships between domains, black arrows indicate within-panel neural or mediator directions, and gray arrows indicate trial-design or longitudinal-mediator workflows. These symbols and arrows are organizing conventions and do not imply uniformly established human causality.

Abbreviations: DAMPs, damage-associated molecular patterns; CBT-I, cognitive behavioral therapy for insomnia; CRP, C-reactive protein; IL-6, interleukin-6; TNF, tumor necrosis factor; PET, positron emission tomography; fMRI, functional magnetic resonance imaging.

What This Review Adds

Recent reviews have separately addressed pain chronification, chronic postsurgical pain, psychological interventions, digital CBT delivery and glial mechanisms.^{2,4,5,12,13,16} The present review links these literatures while keeping clinical efficacy, mechanistic plausibility and prevention hypotheses analytically separate.

The review addresses these gaps through three connected additions (Table 1). First, it distinguishes clinical efficacy, mechanistic plausibility, prevention hypotheses and disease-modification claims, so that CBT is neither reduced to supportive care nor overestimated as an established glial intervention. Second, it maps CBT components to candidate mediators, including catastrophizing, fear avoidance, sleep disturbance, autonomic arousal and peripheral inflammatory tone, while identifying where evidence is indirect.^6–8,11,15 Third, it converts the synthesis into a risk-stratified, early and mechanism-embedded trial agenda. The framework therefore makes three linked but testable propositions: specified CBT components may change psychological and behavioral mediators; mediator changes may influence stress physiology, sleep, autonomic regulation and peripheral inflammatory tone; and these trajectories may be associated with persistent-pain risk in selected acute-to-persistent contexts. None of these propositions establishes direct human glial modulation or a universal mechanism across chronic pain conditions.^5,9–11

Table 1.

Added Value of This Review Relative to Adjacent Literature

Adjacent Literature	Established Contribution	Evidence Type	Remaining Gap	What This Review Adds
Pain chronification and chronic postsurgical pain literature1–4,12,13,17,18	Define the acute-to-chronic transition, CPSP mechanisms, prevention uncertainty, perioperative risk factors and transitional pain-service context.	Narrative reviews, mechanistic reviews, systematic reviews/meta-analyses and prevention-focused syntheses.	Often do not specify how CBT components should be linked to neuroimmune hypotheses or tested as mechanism-embedded early interventions.	Places CBT within a time-sensitive chronification framework and separates prevention hypotheses from established treatment effects.
Glial, neuroimmune and central-sensitization literature9,10,16,19–24	Recognize the neuroimmune roles in central sensitization and chronic pain, including representative evidence of microglial, astrocytic, P2X4 and chemokine-mediated neuron-glia mechanisms.	Mechanistic and translational review literature, including human PET/imaging evidence with explicit interpretive caveats.	Do not show that CBT directly inhibits human glial activation; human neuroinflammation markers remain technically and biologically indirect.	It uses the rationale of neuroimmune and glial biology, but not too much as it is based on animal, cellular, peripheral-marker or imaging evidence to explain the CBT-mediated effects of glial modulation.
CBT and psychological-therapy outcome literature5–8,25–28	Support benefits for interference, disability, distress, coping, sleep and function, with pain-intensity effects often more modest or comparator-dependent.	Cochrane/systematic reviews, network meta-analyses, randomized trials, CBT-I reviews and postoperative CBT meta-analysis.	Usually do not establish biological mediation, prevention of chronification or disease modification.	Maps CBT components to candidate mediators and distinguishes clinical efficacy from mechanism, prevention and disease-modification claims.
Psychoneuroimmune and biomarker literature11,29–34	Suggest that psychosocial and sleep-focused interventions can alter selected peripheral immune or inflammatory markers in some settings.	Systematic reviews/meta-analyses, network meta-analysis and controlled or randomized biomarker studies.	Peripheral immune change cannot be assumed to reflect central neuroinflammation or glial-cell state.	Treats biomarkers as repeated mechanistic probes for future mediation trials rather than surrogate evidence of central glial modulation.
Digital, perioperative and scalable-delivery literature25,35–41	Show feasibility, access advantages and implementation barriers for remote, digital, perioperative or scalable behavioral pain interventions.	Trial protocol, randomized trial, systematic reviews/meta-analyses, scoping reviews and implementation-focused review literature.	Adherence, equity, risk enrichment, engagement, implementation barriers and active comparators remain unresolved.	Translates the synthesis into early, risk-stratified, component-specified and actively controlled trial designs.

The framework is clinically applicable and experimentally falsifiable. It also advocates CBT as a component of multimodal pain care, specifies which mechanistic claims are testable, and specifies the biomarkers, comparators and longitudinal mediation designs that should be established before prevention or disease-modification language is justified.

Search Strategy and Evidence Selection

This structured narrative review used PubMed/MEDLINE as the principal database. PubMed was selected as a common biomedical source spanning clinical pain trials, experimental neuroimmune research and human biomarker studies, consistent with a question-focused narrative synthesis rather than an exhaustive inventory of psychological treatments. Fielded queries and PMID-based record handling supported reproducible retrieval and verification; nevertheless, a single-database search may omit relevant psychological and implementation literature. January 2014 defines a complete-calendar-year starting point for a contemporary evidence window of more than twelve years, encompassing mechanistic work and subsequent clinical and translational evidence relevant to the review’s trial-design questions. This is a scope boundary, not a biological turning point: earlier work informs the conceptual background through cited syntheses, but was not comprehensively searched. The searches were updated on September 10, 2026, and covered publications from January 1, 2014, through September 10, 2026. Five title/abstract query blocks were used to address: (1) acute-to-persistent pain transition; (2) neuroimmune mechanisms combined with pain or nociception; (3) CBT or psychological therapy combined with chronic, postsurgical or perioperative pain; (4) psychoneuroimmune pathways combined with pain-related terms; and (5) digital or telehealth CBT combined with pain. Citation chasing and selected landmark publications were used to supplement database retrieval. The review was designed as a structured narrative review rather than a systematic review or formal scoping review; accordingly, no quantitative pooling or formal risk-of-bias scoring was undertaken.

The pain-transition block included pain chronification, acute-to-chronic pain, chronic postsurgical pain, persistent postsurgical pain and pain persistence. The neuroimmune block combined neuroinflammation, neuroimmune, central sensitization, microglia, astrocytes, glial, BDNF, TrkB, cytokines or chemokines with pain, nociception or nociceptive terms. The CBT block combined cognitive behavioral therapy, cognitive behavioural therapy, CBT, psychological therapy or psychological intervention with chronic-pain, postsurgical, perioperative, preoperative or postoperative terms. The psychoneuroimmune block combined CBT or psychosocial terms with immune function, CRP, IL-6, TNF, inflammation, stress physiology, autonomic or HPA-axis terms and pain-related terms. The digital-delivery block combined CBT with digital, internet, online, telehealth or telemedicine terms and pain. The complete Boolean search strings, search fields, date limits and retrieval counts are provided in Supplementary Methods S1.

Sources were selected for narrative synthesis when they addressed at least one of the following evidence domains: acute-to-chronic pain transition, chronic postsurgical pain risk, neuroimmune or glial mechanisms, brain-network or cognitive-affective pain processing, CBT or CBT-based psychological intervention outcomes, psychoneuroimmune biomarkers, perioperative prevention hypotheses, risk phenotyping, or digital and scalable delivery. Priority was given to systematic reviews, meta-analyses, randomized trials, prospective cohorts, human mechanistic studies, and animal or cellular studies with a clearly defined mechanistic role. Cochrane reviews, controlled CBT studies, human PET or other neuroimaging studies, and cell-specific glial or neuroimmune research were retained when directly relevant to the corresponding claim.^{5,10,12,19,25} Case reports, non-peer-reviewed opinion articles, small uncontrolled studies without relevant mechanistic endpoints, and sources outside the review’s pain-transition or CBT scope were not used as core evidence.

The synthesis used evidence mapping as an organizing procedure within the structured narrative review, rather than as a claim of formal scoping-review methodology. Retrieved sources were categorized by evidence domain, study type and interpretive role (Table 2). Fine-grained mechanistic or methodological claims were based on full-text sources when available; information available only from abstracts or bibliographic records was used only for general statements about study topic, design and principal conclusion. This distinction limits mechanistic interpretation when the relevant methods, subgroup analyses or supplementary materials were not available.

Table 2.

Evidence Map Linking Reference Domains to Claim Boundaries

Evidence Domain	Representative References	Evidence Role/Dominant Evidence Base	Citation Role	What the Evidence Supports	Boundary of Interpretation
Pain chronification and CPSP transition	[1–4, 12, 17, 18, 42–46]	Chronification framework; reviews, cohorts and mechanistic syntheses	Chronification framework	Acute-to-chronic transition involves biological, cognitive-affective and behavioral processes.	Does not define a single universal chronification pathway.
Perioperative prevention and early window	[13, 14, 39, 47–55]	Prevention hypothesis; trials, reviews and protocols	Prevention-hypothesis framing	Early perioperative psychological and transitional pain approaches are feasible and clinically relevant.	Prevention of chronification remains an unproven clinical hypothesis.
Neuroimmune activation and central sensitization	[9, 19–21, 31, 33, 56–63]	Biological plausibility; translational and human associative evidence	Biological plausibility	Neuroimmune signaling, inflammatory mediators and sensitization contribute to pain persistence.	Peripheral markers do not directly prove central neuroinflammation or glial modulation.
Glial and neuron-glia mechanisms	[10, 16, 22–24, 64–74]	Experimental causality; animal, cellular and pharmacological studies	Cellular mechanism boundary	Microglia, astrocytes, chemokines and BDNF-related pathways can shape experimental pain.	These studies do not show that CBT directly inhibits human glia.
Brain networks and cognitive-affective processing	[75–86]	Supraspinal mediator context; human imaging, behavioral and review evidence	Supraspinal mediator context	Pain involves prefrontal, limbic, salience and descending modulatory networks.	Most evidence is associative or condition-specific.
CBT and psychological therapies	[5–7, 25–27, 35, 87–102]	Clinical efficacy; systematic reviews, meta-analyses and randomized trials	Clinical efficacy evidence	CBT improves interference, disability, distress, coping, sleep and function in selected pain populations.	Average pain-intensity effects are often modest and comparator-dependent.
Psychoneuroimmune pathways	[8, 11, 28–30, 32, 34, 58, 99, 100, 103–107]	Indirect biomarker rationale; randomized and systematic biomarker evidence	Indirect biomarker rationale	Psychosocial and behavioral interventions may alter peripheral immune markers in selected settings.	Immune-marker change should not be equated with glial modulation.
Risk factors and confounders	[15, 101, 108–113]	Phenotyping and confounding context; cohorts, meta-analyses and reviews	Phenotyping and confounding context	Catastrophizing, fear avoidance, sleep, mood, opioids and prior pain can shape outcomes.	These variables may be mediators, moderators or confounders.
Digital and scalable delivery	[36–38, 40, 41, 92, 102, 114, 115]	Implementation feasibility; trials, reviews and implementation studies	Implementation feasibility	Digital and telehealth approaches can improve access and support early delivery.	Adherence, engagement and equity remain major implementation constraints.

The narrative synthesis and citation choices were guided by the evidentiary role of each source. Chronic-pain trials were used to support clinical-efficacy claims; animal and cell-based studies were treated as plausible mechanistic explanations rather than direct evidence that CBT alters glial activity; and peripheral biomarker findings were interpreted as indirect psychoneuroimmune plausibility rather than evidence of central glial modulation. The resulting framework is intended to clarify evidence boundaries and generate testable trial questions, not to provide a quantitative estimate of treatment effects.

Evidence Grading and Claim Boundaries

Because the included studies answer different questions, the evidence was classified by evidentiary role rather than placed on a single ordinal A-E scale (Table 3). Clinical efficacy was informed primarily by systematic reviews, meta-analyses and randomized trials; prognostic and risk-phenotyping claims by prospective cohorts and related observational evidence; human mechanistic claims by imaging, biomarker and experimental studies; biological causality by animal, cellular and pharmacological studies; and implementation claims by protocols, delivery studies and implementation-focused reviews. This question-specific classification avoids treating a clinical outcome estimate, an experimental causal mechanism and a feasibility signal as interchangeable levels of evidence.

Table 3.

Evidence Grading and Claim Boundaries

Question	Evidence Base/Role	Supported Statement	Unsupported Overstatement
Neuroimmune mechanisms	Experimental, translational and human associative evidence9,19–21,31,33,56–63	Neuroimmune signaling contributes to central sensitization and pain persistence.	All pain chronification is driven by a single inflammatory pathway.
Glial causality	Animal, cell-specific, pharmacological and selected human imaging evidence10,16,22–24,64–77	Microglial and astrocytic pathways can be causal in experimental pain models.	CBT directly inhibits human glial activation.
CBT efficacy	Systematic reviews, meta-analyses and randomized trials5–7,25–28,35,87–91,93–98	CBT improves interference, disability, distress, coping, sleep and function.	CBT is a potent analgesic or proven disease-modifying therapy.
Immune markers	Randomized trials, systematic reviews/meta-analyses and biomarker studies8,11,29,30,32,34	Psychological interventions may influence peripheral immune markers in selected contexts.	Peripheral cytokine changes prove central neuroinflammation or reversed glial modulation.
Early prevention	Prospective perioperative studies, trials, protocols and implementation evidence13,14,25,35,39,47–55	Early CBT is a candidate prevention strategy requiring direct testing.	Early CBT is proven to block pain chronification.

The strongest support for CBT concerns clinical outcomes, particularly interference, disability, distress, coping, sleep and function, whereas the evidence for direct human glial modulation remains insufficient.^5,25,26 Neuroimmune signaling and glial pathways provide biological plausibility for pain persistence, but much of the causal evidence comes from experimental or translational work.^9,10 Peripheral biomarker and neuroimaging findings answer association or mechanistic-probe questions and should not be treated as direct proof of central glial change. Early CBT remains a prevention hypothesis requiring prospective testing rather than an established preventive effect. These evidence statements therefore remain separate instead of being collapsed into one mechanistic hierarchy.

The most important boundary concerns causal language. It is reasonable to state that microglial and astrocytic pathways contribute to pain-related processes in selected neuropathic-pain models,^9,10 that CBT improves outcomes in chronic pain,⁵ and that psychosocial treatment may affect some immune parameters.¹¹ It is not established that CBT inhibits human microglia, reverses central neuroinflammation or prevents the transition to persistent pain. Accordingly, claims should be labeled as established, supported, plausible, indirect, unconfirmed or uncertain according to the evidence available.

The second boundary is intervention specificity. CBT tends to be considered as a single exposure, but the protocols vary greatly. Downstream effects of cognitive restructuring, graded exposure, behavioral activation, relaxation, sleep-focused CBT, attention retraining and skills-based pain coping can differ. A statement regarding CBT and hypothalamic-pituitary-adrenal (HPA)-axis regulation does not necessarily imply that an internet CBT trial of chronic disease will support it. Similarly, a statement about fear avoidance does not automatically mean that a trial on insomnia will support it. The interpretation at the mechanistic level requires component-level specificity.^7,8,15,87

The third boundary concerns the hierarchy of outcomes. Pain intensity is clinically important, but it is not the only or necessarily the most sensitive outcome for CBT. Psychological trials more consistently detect changes in pain interference, disability, distress, sleep, self-efficacy and activity. These outcomes reflect the functional and behavioral consequences of pain and should not be equated with a change in nociceptive biology. CBT may modify pain-related functioning and psychological adjustment, whereas its effects on nociceptive mechanisms and neuroimmune processes remain incompletely defined.^5,25,26,87

Neuroimmune Mechanisms of Pain Chronification

Neuroimmune activation is one biological contributor to pain chronification. Tissue injury can trigger release of damage-associated molecular patterns (DAMPs), ATP, growth factors, chemokines and cytokines that activate nociceptors and innate immune pathways. Inflammatory mediators can sensitize peripheral terminals, alter dorsal root ganglion excitability and shape spinal synaptic transmission. At the spinal level, immune and glial mediators may support disinhibition, excitatory amplification and persistent central sensitization in selected models.^9,20,21,56

Central sensitization is not an isolated phenomenon. It can be seen as a result of the relationship between neurons, microglia, astrocytes, macrophages and other cells of the peripheral immune system with endothelial cells. The literature on neuroinflammation and chronic pain states that cytokines, chemokines, oxidative stress, BDNF signaling and phenotypes of immune-cells are able to both facilitate the process of pain and alleviate it depending on the situation.^9,21,56,57 Such facts will give the dynamic perspective that the immunity response could be protective, maladaptive or resolving in various phases but not just a pro-inflammatory one.

One of the most well-characterized causes of experimental neuropathic pain is microglia, but not all models of neuropathic pain are microglia-dependent. P2X4 receptors, CX3CR1, CSF1R, p38 MAPK, BDNF-TrkB, chemokines and cytokine signaling pathways can be used to modify dorsal horn excitability and pain behavior in animal models.^10,16,22,64 The role of astrocytes and broader neuron-glia interactions seems especially relevant in maintenance phases by glutamate transport, cytokine release, blood-brain barrier interaction, metabolic support and spinal-cord cellular heterogeneity.^23,65–67

Human evidence is more cautious. Positron emission tomography (PET) and imaging approaches based on the translocator protein (TSPO) have been used to study possible neuroinflammatory signals, but their technical and biological interpretation remains limited. TSPO is not a direct indicator of microglial response, and peripheral cytokines do not directly establish central neuroinflammation or glial-cell state. Human neuroimmune findings therefore support plausibility and motivate mechanistic experiments, but they cannot be interpreted as evidence that CBT inhibits glial activation.^19,75–77

These mechanisms define a biological target space rather than a demonstrated CBT mechanism. A more defensible model is that CBT may influence upstream psychological and behavioral processes, including threat, arousal, sleep disturbance and avoidance, which could alter autonomic tone, HPA-axis activity and peripheral inflammatory milieu.^6–8,11,15 This pathway remains indirect and does not establish central glial regulation. Mediation designs with repeated psychological, biological and clinical measurements, and where feasible imaging or other central neuroimmune endpoints, are needed before central glial effects can be inferred.

The timing of immune signaling is also relevant. Acute inflammatory responses may support repair and pain resolution, whereas sustained or dysregulated immune signaling may support sensitization. This distinction precludes a simplistic anti-inflammatory interpretation of CBT. If a behavioral intervention decreases stress-related inflammatory tone, this does not imply that it should squelch all immune activity after injury. The more plausible aim is normalizing maladaptive feedback loops between pain, sleep, arousal, and immune signaling. That is why perioperative trials should assess trajectories instead of single biomarker values; a single postoperative cytokine measurement cannot distinguish adaptive repair from maladaptive chronification risk.^9,11,42,56

Brain Networks, Cognitive-Affective Amplification, and Descending Control

Pain chronification also includes supraspinal reorganization. Persistent pain has been associated with alterations in prefrontal, anterior cingulate, insular, amygdala, hippocampal, thalamic and descending modulatory systems.^75,76,78,79 These networks integrate nociceptive signals with salience, emotion, prediction, memory, interoception and behavioral control, and provide a plausible substrate through which cognitive-affective interventions may change pain experience and function without directly altering immune cells.

The prefrontal cortex is involved in appraisal, expectation, attention and behavioral control. Cortico-limbic circuits link pain to emotional learning, fear and motivation. The amygdala and hippocampal systems may be relevant to the transition from acute pain to persistent pain because they participate in threat learning and memory consolidation.^43,80–82 When pain becomes associated with danger, avoidance and helplessness, cognitive-affective networks may amplify pain-related responses and weaken adaptive descending control.

This network perspective helps explain why CBT may improve pain interference more consistently than pain intensity. CBT can reduce catastrophizing, alter avoidance behavior, improve sleep routines and increase adaptive activity. These changes may alter the meaning and behavioral consequences of pain even when nociceptive input is not demonstrably changed. A randomized neuroimaging trial in fibromyalgia supports a condition-specific proof of principle linking reduced catastrophizing with changes in pain-relevant brain processing.⁵ It does not establish a universal neuroimmune mechanism across chronic pain conditions.^6,78,83

Brain networks and spinal processing are connected through descending modulation. Sleep loss, fear and depression may alter the balance between inhibitory and facilitatory descending control.^75,78 CBT components could influence this balance by reducing threat, improving sleep and increasing perceived control.^5,6 This remains a mechanistic hypothesis until psychological mediators, descending-modulation indicators, inflammatory mediators and clinical outcomes are tested longitudinally.

Clinical Evidence for CBT in Chronic Pain

CBT is well supported by clinical evidence in chronic pain, but the extent of benefit should be defined exactly. The Cochrane review of psychological therapies to treat chronic pain and network meta-analyses on low back pain indicate that there are benefits in disability, distress, coping and interference.^5,6,26,88 Mean effects on the intensity of pain tend to be small to moderate and differ depending on the comparator. Mechanistic sophistication ought not to suggest analgesic potency more than the outcomes literature.

This trend is supported by the recent randomized trials and meta-analyses. The CBT-based methods may be effective in treating chronic low back pain among older veterans with chronic pain, high-impact chronic pain treated via telehealth or online delivery, and subacute or chronic low back pain populations.^25,27,87,89 They have clinically relevant effects on selected outcomes but do not equal reversal of central sensitization or disease modification.

Behavioral and psychological treatment has also been studied in fibromyalgia, irritable bowel syndrome, headache, migraine, tension-type headache and chronic musculoskeletal pain, but these conditions differ in mechanisms, clinical outcomes and treatment components.^{7,84,85,90–92} For example, CBT-I in chronic musculoskeletal pain may primarily target sleep and related stress physiology, whereas exposure-based CBT may target fear avoidance and disability. Findings from one condition or CBT component should not be generalized automatically to all chronic pain conditions.

The online and distance-based CBT is a solution that brings an increase in the access, but it also comes with its own caveats. The use of internet-based and mobile CBT, guided internet CBT, telehealth CBT, electronic headache treatments, and digital pain management can be used to enhance the reach although adherence, therapeutic alliance, patient selection, and digital literacy will have some influence on the results.^{25,35–38,114} These models of delivery are promising as they are useful when early intervention is possible, however, only the fact that an intervention is delivered in a digital form does not mean that it is preventive or active.

The clinical evidence hence leads to a balanced conclusion. CBT is beneficial and based on evidence particularly when it comes to functional results and psychological distress. It does not serve as an independent treatment of chronic pain, and the ongoing trials do not confirm CBT as a glial-targeting therapy. The most plausible role that it plays in the process of pain chronification is a component-specific, risk-stratified and mechanism-informed intervention which is incorporated into multimodal care.

The biological hypothesis is more testable with a component-specific model. Threat appraisal, catastrophizing and expectancy should be associated with cognitive restructuring. Graded exposure must be connected to fear avoidance, protective behavior and functional restoration. The activity patterns, mood, social reinforcement and return to work should be related to behavioral activation. Sleep-based CBT needs to be associated with insomnia, fatigue, autonomic arousal and inflammatory tone. Sympathetic activation and stress recovery should be associated with relaxation, breathing skills and biofeedback. These mappings are not sufficient evidence of biological mediation, but they make clear predictions on the design of trials. They also do not suffer the internal inconsistency of making fine-grained biological claims and treating CBT as a black box.^{6–8,15,87,108}

This is also true in the case of selection of patients. The CBT focus on a patient who has severe insomnia as the dominant risk factor will be different to the one with the fear avoidance post-surgery as the dominant risk factor. A highly catastrophizing and depressive patient can be restructured cognitively, behaviourally activated, and mentally cared by the mental health provider. The opioid-treated chronic low back pain patient can be combined with the skills of opioid stewardship and mindfulness or cognitive-behavioral therapy. This model of treatment assignment is better fitted to the biopsychosocial than the single universal CBT package.^7,87,103,109

Psychoneuroimmune Pathways Linking CBT to Pain Chronification

The most defensible psychoneuroimmune model is indirect and upstream. CBT may reduce threat appraisal, catastrophizing, fear-related avoidance, sleeplessness, arousal and passive coping. These psychological and behavioral changes may influence stress physiology, autonomic balance, activity, sleep architecture and peripheral inflammatory tone. In turn, these processes may affect the processing of nociceptive and immune signals, but this sequence remains a testable hypothesis rather than a demonstrated causal pathway.^11,15,29,30

Meta-analytic data indicate that psychosocial interventions may have an effect on immune-system functioning, but the results depend on the type of intervention, population, timing and biomarker.^11,29 The evidence that is specific to pain is more limited though relevant. Research in fibromyalgia, low back pain, chronic pelvic pain and insomnia-related interventions indicates that behavioral treatment can be associated with inflammatory markers in selected groups.^{30–32,58,104} These results explain why immune endpoints are measured as indirect mechanistic probes, yet they do not prove central glial modulation or determine the cellular origin of any central signal. In the IMPACT biomarker substudy of 114 women with chronic low back pain and depressive symptoms, acceptance and commitment therapy or behavioral activation added to usual care improved selected clinical outcomes, but biomarker differences did not survive multiple-testing correction. Only 69 participants completed post-treatment assessment, and the eight-week biomarker window limits conclusions about longer-term effects; these findings do not establish an absence of biological change.¹¹⁶

Sleep is another important pathway; sleep disturbance predicts chronic postsurgical pain and is prevalent in chronic pain populations.^7,8,47,110 Interventions targeting insomnia via cognitive behavioral therapy for insomnia (CBT-I) and other sleep focused interventions can improve sleep, which in turn may reduce stress-system activation and inflammatory tone. However, the link from CBT-I to prevention of pain chronification is still a hypothesis that has not been tested directly. In a secondary analysis of 223 participants with chronic low back pain, pooled CBT and Empowered Relief analyses identified statistical indirect effects through reduced pain interference and catastrophizing and increased self-efficacy, but not pain intensity, on sleep improvement. Concurrent self-report measurements precluded clear temporal ordering; these results neither establish a CBT-specific causal pathway nor demonstrate immune mediation.¹¹⁷

The other way is fear avoidance and catastrophizing. The disability, negative affect and pain intensity are the two factors that have been associated with the fear-avoidance model in terms of the relationship between pain catastrophizing and the fear of pain.^6,15,108 Catastrophization reduction or graded re-engagement CBT elements can break the vicious circle of behavioral processes leading to pain-related disability. This process has a clinical possibility which is more plausible than the claims made directly on the suppression of microglial cells.

The psychoneuroimmune model also needs to consider bidirectionality. Inflammation, pain and sleep disruption can make mood and cognition worse; mood, arousal and avoidance can make pain and inflammation worse. CBT may work by changing feedback loops instead of focusing on a single molecular pathway. This is why future trials will require repeated measurements and mediation analysis.

Early Intervention Windows and Clinical Feasibility

The early intervention window is essential to any prevention or disease-modification claim. A pragmatic framework distinguishes three stages. The first is preoperative or pre-injury risk identification, when baseline pain, sleep, mental health, opioid exposure and catastrophizing can be measured. The second is the acute phase from 0 to 14 days after injury or surgery, when nociceptive input, inflammation and recovery expectations are rapidly evolving. The third is the subacute consolidation phase from approximately 2 to 12 weeks, when avoidance, sleep disturbance and persistent pain-related beliefs may stabilize.^3,4,12–14 These windows are proposed for testing, not evidence that CBT prevents persistent pain.

After 3 months, many definitions of chronic pain are met. Intervention only after that point may still enhance function, but no longer tests interruption of chronification. Trials of perioperative psychological interventions, psychological prehabilitation and digital perioperative CBT are thus important since they shift treatment earlier in the trajectory.^39,48–51 The SurgeryPal protocol shows how a digital perioperative CBT intervention can be developed to test if early behavioural treatment decreases transition from acute to chronic postsurgical pain.³⁹

The possibility is the stratification of risk. It may be not efficient to use CBT on all patients who undergo surgical or injury operations since most of them are not in a constant state of pain. The high-risk profile includes the presence of acute pain, pre-existing pain, sleep disturbance, catastrophizing, depression or anxiety, and exposure to opioid, history of pain and poor prognosis.^{15,17,18,47,109,111} Such characteristics can be measured before the operation or after the operation and applied to enriching prevention experiments.

There are also practical limitations of the early-window hypothesis. The patients in acute perioperative stage can be tired, medicated, distressed or overwhelmed. Interventions should be short, modular and flexible. Digital tools can assist with access, but they need to refrain low adherence and superficial engagement. Integration with transitional pain services, rehabilitation and analgesic optimization will probably be required to implement it in real life.^{13,14,36–38,40}

The clinical appeal of early CBT lies in the fact that it addresses modifiable risk processes prior to the establishment of persistent pain. Its preventive worth has not been established and thus needs to be proven by trials that are constructed around timing, risk enrichment, active controls and longitudinal mechanisms.

A feasible perioperative pathway might start with a screening at the surgical scheduling or pre-anesthesia assessment. Catastrophizing, sleep disturbance, past pain, opioid exposure, depression, anxiety and recovery expectations could be identified by brief instruments. A modular intervention can be given to patients whose risk is above a certain threshold before surgery and short reinforcement sessions during hospitalization and digital follow-up after discharge. This route is more realistic than long traditional CBT in the acute post-operative stage. It also fits in with transitional pain services that already seek to connect acute postoperative care and attempts to minimize chronic pain risk.^{13,14,39,50,105,111}

The pathway is not a substitute to the optimization of analgesics. Instead, it must be integrated with multimodal analgesia, rehabilitation, sleep management and opioid stewardship. This is important since drugs may confound both outcomes and mechanisms. In case there is a difference in exposure to opioids, regional anesthesia or non-opioid analgesics between groups, the results on pain or inflammatory markers cannot be confidently attributed to CBT. A reasonable trial should thus standardize analgesic protocols where feasible and document medication exposure at an adequate level of detail to allow sensitivity analyses.^{28,47,50,52,87}

Confounding Factors and Potential Negative Effects

There are a number of confounders that need to be identified. The use of analgesic drugs will have an impact on the levels of pain, sleep and mood, as well as inflammation and recovery in terms of function. Neuroimmune state and CBT results can be impacted by NSAIDs, regional anesthesia, opioids, gabapentinoids and antidepressants.^{28,50,52,87,109} It is possible that these effects were not caused by CBT, but the effects of the medication.

Mental health disorders are also a part of the comorbid condition. The presence of depression, anxiety and high negative affect, trauma symptoms, and clinical signs of psychological distress can influence the reporting of pain, involvement in treatment, inflammatory reaction to behavioral therapy.^{15,18,103,105,109} These diseases cannot be considered as an annoyance factor; they can be able to detect phenotypes that have varying responses to CBT elements.

The previous experience of pain and sleep disorder may be biased. The patients with the pre-existing pains can have already developed sensitive systems and a well-developed concept of pain prior to the index surgery or injury. The disturbance in sleep is capable of increasing the level of pain, as well as deteriorating mood and changes in inflammatory indices. Any trial that does not take into consideration baseline pain and sleep risks confounding the effect of treatment on the patient.^7,8,47,110

Possible adverse effects are worth talking about. Poorly timed exposure-based tasks can temporarily elevate pain or fear. The intensive self-monitoring can add to the load or rumination. A purely cognitive framing may feel invalidating when patients hear it as implying that pain is not real. Digital CBT may have low adherence, reduced therapeutic alliance and inequitable access. Patients with suicidality, severe depression, cognitive impairment, active trauma symptoms or complex opioid use may require multidisciplinary care rather than stand-alone CBT.^{36–38,41,103,109}

These constraints are in favor of a specific, phenotyped and combined clinical position. CBT is not an all-purpose or biological remedy, which should be sold as part of the multi-modal treatment with its targets, strength and mode of delivery to fit the risk profile of patients.

Future Trial Designs

The future studies need to go beyond the general recommendation of more RCTs and focus on the hypothesis in this review, which is that CBT as an early intervention, risk-based, and component-specific treatment can have positive outcomes on mediators of change before a person experiences the persistence of pain (Table 4). Prevention hypotheses should be tested by recruiting patients with high levels of catastrophizing, high levels of acute pain, disturbed sleep, previous experience of pain, exposure to opioids or depression and anxiety disorders. The randomization may be done preoperatively, when it is possible, or in the initial days following the injury or operation. Intervention must start at an early stage, follow-up in the first two weeks after the surgery, and be followed up during the 2–12 week subacute phase.^{14,15,39,48,49,111}

Table 4.

Mechanism-Embedded Clinical Trial Recommendations

Component	Recommended Design	Rationale
Population	High-risk acute or perioperative pain patients	Avoid dilution by low-risk spontaneous recovery.
Timing	Preoperative risk identification, 0–14 day acute phase, 2–12 week consolidation	Directly test the proposed intervention window.
Intervention	Component-specified CBT modules	Link cognitive, exposure, sleep and activation modules to mechanisms.
Comparator	Active education, mindfulness, attention control or enhanced usual care	Control expectancy, attention and contact time.
Clinical endpoints	3- and 6-month persistent pain, interference, function, opioid use	Test chronification-related outcomes without presuming prevention efficacy.
Mechanistic endpoints	Catastrophizing, fear avoidance, sleep, autonomic/HPA markers, CRP, IL-6, TNF, fMRI or PET where feasible	Permit mediation and moderation analyses while avoiding peripheral-to-central overinterpretation.
Safety endpoints	Dropout, transient pain/fear exacerbation, burden, perceived invalidation	Balance efficacy claims with patient-centered harms.

The intervention should be component specified; one module might target threat appraisal and catastrophising, another reduce fear avoidance via graded exposure and activity pacing, a sleep module might target insomnia and circadian instability, relaxation or breathing modules might target sympathetic arousal, behavioural activation might facilitate functional recovery etc. Each module should have a pre-specified mechanistic end-point rather than being bundled together under the generic CBT label.^6–8,15,27

Comparators must be believable. The additional care can also be overestimated as a result of the increased attention and expectancy to CBT. Comparators may be active in terms of pain education, supportive counseling, mindfulness, online learning or even digital education or attention control. In trials, it is necessary to assess the credibility of treatment, compliance with the therapy, therapeutic relationship, and completion of modules (in particular, for the digital format).^25,35–38

Clinical endpoints should be persistent pain at 3 and 6 months, interference of pain, functionality, resumption of work or activity, opioid consumption, sleep, emotional distress and quality of life. Catastrophizing, fear avoidance, sleep quality, autonomic markers, HPA-axis markers, CRP, IL-6, TNF and, wherever possible, functional magnetic resonance imaging (fMRI) or PET measures that are relevant to neuroinflammatory hypotheses should be mechanistic endpoints.^{11,19,29,75–77} These tests must be repeated with time in order to allow mediation analyses to test the temporal ordering. Peripheral biomarkers and imaging signals ought to be viewed as mechanistic probes but not as validated surrogates of central glial modulation.

The mediation and moderation must be defined in statistical plans prior to the trial launch. Mediation may be used to test whether psychological changes precede biomarker changes, and whether both of these are followed by pain outcomes. Moderation may be used to test whether baseline phenotype determines response. These designs would help to establish whether CBT is limited to symptomatic support in this setting or whether early, targeted CBT is associated with mediator changes that predict lower risk of persistent pain.

Lastly, it is important to note that the trial must report on harms and burdens. It is not uncommon to think of behavioral intervention as being a harmless process and in this case burden, momentary worsening of symptoms, drop out and invalidation are also clinically significant. Future reviews would be more balanced and helpful with the reporting done transparently.

There are a number of statistical design characteristics that are particularly relevant. First, sample-size calculations must be founded on persistent pain or interference at 3 to 6 months, and not early postoperative pain. Second, the primary mechanism should be pre-defined in trials, like catastrophizing, sleep or fear avoidance, as opposed to measuring numerous biomarkers without hierarchy. Third, mediation analysis ought to take into consideration time order: psychological mediators ought to change prior to changes in biomarkers, and changes in biomarkers ought to precede chronic pain outcomes when making a peripheral biological mediation claim. Fourth, moderation analysis is supposed to check whether baseline phenotype alters response since the average treatment effect can mask benefit in high-risk subgroups. Fifth, dropout and non-adherence need to be addressed openly, particularly with online interventions where the loss rate may be quite high.^{15,25,27,36,39,87}

A trial can be designed with the three-arm structure, that is, increased care as usual, pain education in the form of a structural match and CBT as component-specific. The subjects would be surgical patients at high risk before operation. The outcomes will be measured on the baseline, acute post operative days, 6 weeks, 3 months and 6 months. Biomarkers would be collected during the early stages of recovery and consolidation subacute, baseline. This model would enable researchers to explore the possibility of whether the psychological or behavioral mediators change after CBT and if they do then whether these changes are associated with changes in peripheral immune system or neural-systems and which one of the two leads to the reduction in the risk of persistent pain. In the absence of this time frame, it will not be possible to interpret mechanistically more than clinically.

The advantage of this design is that it will also be useful in the case of negative results. It can demonstrate that the timing was not timely, risk enrichment did not happen and that the CBTs used were not well matched with the patient phenotype and the immune pathway proposed by the researcher as the mediator.

Conclusions

Pain chronification is a dynamic process influenced by neuroimmune activation, central sensitization, brain-network remodeling, cognitive-affective learning, sleep and behavior.^1–5,9,75 CBT is clinically useful in chronic pain, especially for pain interference, disability, distress, coping, sleep and function.^5,25,26,87 The available evidence does not justify presenting CBT as an established preventive, glial-targeting or disease-modifying therapy.

The more productive conclusion is that CBT may indirectly influence the risk or maintenance of persistent pain through psychoneuroimmune pathways involving threat appraisal, catastrophizing, fear avoidance, stress physiology, sleep, autonomic balance and peripheral inflammatory tone.^11,15,29,30 This hypothesis is clinically important because it generates testable predictions without implying that peripheral inflammatory change proves central glial modulation or applies uniformly across chronic pain conditions.

Future studies should examine early, risk-stratified, component-specific and actively controlled CBT models with clinical, biomarker, neuroimaging and mediation endpoints.^25,35,39,87 This approach is congruent with the evidence currently available: the psychoneuroimmune framework can organize intervention hypotheses for selected acute-to-persistent pain trajectories, but it is not a universally established mechanism or a proven preventive treatment.

Funding Statement

This study was supported by Sichuan Science and Technology Program (2023YFS0254) and Sichuan Science and Technology Program (2022YFS0631).

Generative AI Statement

The authors used Gemini-3-Pro-Image (Google AI) solely to assist with figure layout and composition. The tool was not used to generate, modify, interpret, or validate any scientific data, results, or conclusions.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

This research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.