Chronic pain after thoracic surgery: mechanisms, risk factors, and limitations of current preventive strategies—a narrative review

Abstract

Background and Objective

Despite advances in surgical techniques and perioperative analgesia, chronic pain after thoracic surgery (CPTS) is a common and clinically significant complication. Its continued prevalence suggests that current preventive strategies remain insufficient. This narrative review aimed to synthesize current evidence on the mechanisms, risk factors, and limitations of existing preventive strategies for CPTS, with a focus on the transition from acute to chronic pain.

Methods

PubMed, Embase, and Web of Science were searched from database inception to March 2026 for English-language evidence on thoracic surgery, chronic postsurgical pain, risk factors, mechanisms, and perioperative interventions. Thoracic-specific systematic reviews, randomized trials, and prospective studies were prioritized and narratively synthesized; mechanistically informative and selected non-thoracic translational evidence was included where directly relevant.

Key Content and Findings

CPTS is a multifactorial condition involving peripheral nerve injury, neuroinflammation, central sensitization, psychological vulnerability, and the evolving postoperative pain trajectory. Preoperative pain and severe acute postoperative pain are among the most reproducible clinical signals, whereas demographic and procedure-related predictors are less consistent. Multimodal and regional analgesia improve acute recovery, but evidence for CPTS prevention remains inconsistent, partly because brief perioperative interventions may not address prolonged or heterogeneous mechanisms. Early persistent pain may therefore provide a clinically relevant window for reassessment and selective escalation of care.

Conclusions

No single intervention reliably prevents CPTS. Standard procedure-specific multimodal care should be combined with longitudinal risk assessment, attention to dynamic pain trajectories, and selective psychological or transitional pain support. Future trials should test externally validated, risk-stratified care pathways rather than isolated short-duration interventions.

Introduction

Chronic pain after thoracic surgery (CPTS), also referred to as post-thoracotomy pain syndrome, is defined as pain that persists or recurs for at least 3 months after surgery, localized to the thoracic incision or its corresponding innervation territory, and not attributable to other causes such as infection or malignancy (1,2). CPTS is widely recognized as one of the most prevalent chronic pain syndromes following surgery, with a reported incidence ranging from approximately 25% to 80% depending on the surgical technique, patient population, and methodological factors (3,4).

Thoracic surgery presents a unique context for chronic pain development. Unlike many other procedures, thoracic operations involve extensive interaction with the chest wall, intercostal nerves, pleura, and respiratory mechanics. Postoperative recovery necessitates repetitive activation of the surgical site through coughing, deep breathing, and mobilization, which may perpetuate nociceptive input during a critical period of neuroplastic change, thereby facilitating the transition from acute to chronic pain (5,6).

Although the transition from open thoracotomy to minimally invasive approaches such as video-assisted thoracic surgery (VATS) has reduced surgical trauma, CPTS remains highly prevalent (7), indicating that a reduction in tissue injury alone is insufficient to prevent chronic pain.

Importantly, CPTS is not a uniform entity. Patients may present with mixed pain phenotypes, including nociceptive pain from tissue injury and neuropathic pain related to intercostal nerve damage; these mechanisms often coexist in the same individual. Further, only a proportion of patients exhibit purely neuropathic pain, highlighting the heterogeneity of underlying mechanisms.

In addition, psychological factors such as anxiety, depression, and pain catastrophizing frequently coexist and are independently associated with persistent pain, supporting the view that CPTS is best understood within a biopsychosocial framework (6,8,9).

Previous reviews have predominantly addressed individual mechanisms of chronic postsurgical pain or summarized specific perioperative analgesic techniques. In the present review, we adopt a complementary perspective by integrating peripheral nerve injury, central sensitization, neuroimmune processes, and psychosocial vulnerability within a temporal framework of pain chronification. Particular emphasis is placed on early persistent pain as a clinically relevant transitional phase and on the potential temporal and mechanistic mismatch between short-duration perioperative interventions and the more prolonged processes underlying chronic pain development. We further translate this framework into a risk-stratified approach to perioperative care, linking patient vulnerability, procedure-specific factors, dynamic pain trajectories, and potential opportunities for escalation of treatment. The objective of this narrative review is therefore not only to summarize current evidence on CPTS, but also to critically examine why existing preventive strategies have produced inconsistent long-term benefits and to identify clinically actionable priorities for future prevention. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2195/rc).

Methods

This narrative review sought to summarize and critically synthesize current evidence on CPTS, including its mechanisms, risk factors, and preventive strategies. PubMed, Embase, and Web of Science were searched from database inception to March 2026 using combinations of Medical Subject Headings (MeSH) and free-text terms related to thoracic surgery, thoracotomy, video-assisted thoracic surgery, chronic postsurgical pain, post-thoracotomy pain, central sensitization, neuroinflammation, risk factors, and perioperative or regional analgesia. English-language clinical studies, randomized trials, prospective cohorts, systematic reviews/meta-analyses, and mechanistically informative translational or preclinical studies were considered. Selected non-thoracic evidence was included only when it directly informed clinical translation, such as psychological intervention or transitional pain care. Case reports, preprints, letters, and studies unrelated to the review objectives were excluded. Potentially relevant titles/abstracts and full texts were screened for topical relevance by the author team. Because this was a narrative review, formal duplicate screening and a study-level risk-of-bias assessment were not under taken. Study selection and synthesis were performed by the authors using a narrative approach, focusing on key mechanisms and clinically relevant findings (Table 1).

Table 1. Search strategy summary.

Item	Specification
Date of search	March 2026
Databases	PubMed, Embase, and Web of Science
Time frame	From database inception to March 2026
Language	English
Core search concepts	Thoracic surgery; thoracotomy; VATS; chronic postsurgical pain; post-thoracotomy pain; central sensitization; neuroinflammation; risk factors; perioperative and regional analgesia
Eligible evidence	Thoracic-specific clinical studies, randomized trials, prospective cohorts, systematic reviews/meta-analyses, and mechanistically informative translational or preclinical studies; selected non-thoracic evidence was used only when directly relevant to clinical translation
Exclusions	Non-English articles, case reports, preprints, letters, and studies unrelated to the review objectives
Selection process	Potentially relevant titles/abstracts and full texts were screened for topical relevance by the author team. Because this was a narrative review, formal duplicate screening and a study-level risk-of-bias assessment were not undertaken
Evidence prioritization	Priority was given to thoracic-specific systematic reviews/meta-analyses, randomized trials, major prospective studies, and evidence that clarified mechanisms, inconsistency, or clinical applicability

CPTS, chronic pain after thoracic surgery; VATS, video-assisted thoracic surgery.

Epidemiology and clinical phenotype

Despite advances in surgical techniques, CPTS remains a clinically significant problem. Compared with VATS, open thoracotomy is associated with a higher incidence of CPTS, particularly among patients with additional risk factors such as extensive resection or preoperative pain (10). Minimally invasive surgical approaches do not eliminate the risk of chronic pain; rather, they appear to alter its clinical presentation, resulting in lower pain severity in some patients while preserving the heterogeneity of the underlying pain mechanisms (7,10,11).

Clinically, CPTS presents with a broad spectrum of symptoms. Pain may be localized to the surgical incision, distributed along the intercostal dermatomes, or experienced as diffuse chest wall discomfort. Neuropathic features, including burning pain, electric shock–like sensations, and sensory disturbances, are present in a subset of patients, although many exhibit mixed pain phenotypes (1,12,13). In addition to somatic symptoms, CPTS is frequently accompanied by psychological comorbidities such as anxiety and depression, which may influence both pain perception and long-term outcomes (14,15).

The relationship between surgical approach and CPTS requires particular consideration in thoracic surgery. Open thoracotomy produces direct chest-wall disruption and may expose intercostal nerves to rib retraction, compression, and traction, whereas minimally invasive approaches reduce but do not eliminate intercostal trauma. Randomized and observational evidence generally demonstrates lower postoperative pain and improved recovery with VATS compared with thoracotomy, although clinically relevant persistent pain continues to occur after VATS (7,10,11,16-18). Importantly, minimally invasive surgery should not be regarded as a uniform exposure. Multiportal VATS introduces several intercostal access sites, whereas uniportal VATS reduces the number of ports but concentrates instrument manipulation through a single intercostal space. Available studies suggest potential short-term pain advantages with uniportal approaches, but robust evidence demonstrating a lower incidence of CPTS remains limited (7,19). Robot-assisted thoracic surgery (RATS) similarly avoids rib spreading but still requires intercostal ports and instrument torque; comparative studies have not consistently demonstrated a long-term pain advantage over VATS (7,19).

Beyond the incision itself, thoracic surgery has several procedure-specific features that may sustain nociceptive input, including intercostal nerve manipulation, pleural injury, chest tube placement, repeated coughing and deep breathing, and early mobilization. Consequently, the reduction in surgical invasiveness modifies rather than abolishes the biological substrate for pain chronification. This may partly explain why CPTS remains prevalent despite the transition from thoracotomy to minimally invasive surgery.

Pathophysiology of CPTS

Intercostal nerve injury: necessary but not sufficient

Intercostal nerve injury is widely considered a primary initiating factor in the development of CPTS. During thoracic surgery, nerves may be subjected to compression, traction, ischemic injury or direct transection due to rib retraction, surgical incision, and chest tube placement (20). Such nerve injury induces abnormal spontaneous activity in primary afferent fibers, characterized by ectopic discharges originating from both the injured nerve site and dorsal root ganglion neurons, which are widely recognized as key contributors to neuropathic pain (21,22). At the molecular level, the altered expression and function of voltage-gated sodium channels, particularly Nav1.7 and Nav1.8, and calcium channels contribute to increased neuronal excitability, lowering activation thresholds and facilitating enhanced nociceptive signal transmission (23,24). Additionally, injured nerves release neuropeptides such as substance P and calcitonin gene-related peptide, which enhance local inflammation and peripheral sensitization (25-27).

However, accumulating evidence suggests that intercostal nerve injury alone cannot fully explain the development of CPTS (8,20). Although nerve injury is considered an important initiating event, persistent pain is influenced by multiple interacting mechanisms, including central sensitization, neuroinflammation, and individual susceptibility (28,29).

Peripheral sensitization: the initiating phase

Peripheral sensitization arises from the inflammatory response to surgical trauma, whereby tissue injury triggers the release of mediators such as cytokines, prostaglandins, bradykinin, and nerve growth factor. These mediators act on peripheral nociceptors to lower activation thresholds and increase excitability, thereby amplifying nociceptive signaling (30,31). Activation of intracellular signaling pathways, including protein kinase A, protein kinase C, and mitogen-activated protein kinase cascades, further enhances nociceptor responsiveness by modulating ion channel activity and gene expression, thereby amplifying nociceptive input during the early postoperative period (31,32). Although peripheral sensitization is essential for acute pain, its contribution to chronic pain depends on whether it triggers sustained central changes.

Central sensitization: the core driver

Central sensitization is widely considered a core mechanism underlying CPTS. It involves increased excitability of neurons in the spinal cord and brain, resulting in the amplification of pain signals (28). Key mechanisms involved include N-methyl-D-aspartate (NMDA) receptor activation, increased intracellular calcium, synaptic plasticity and long-term potentiation, and impaired descending inhibitory pathways (33-35). Importantly, central sensitization may be established early in the postoperative period. Clinical studies have consistently demonstrated that both the intensity and qualitative characteristics of acute postoperative pain, particularly neuropathic features, are strongly associated with the development of persistent postsurgical pain. These findings highlight the importance of early pain phenotyping in determining long-term outcomes (29,36,37).

Neuroinflammation: sustaining the system

Neuroinflammation plays a crucial role in maintaining central sensitization. Following surgical injury, microglia and astrocytes become activated and release pro-inflammatory cytokines such as interleukin-1β, interleukin-18, and tumor necrosis factor-α (30,38). These mediators enhance neuronal excitability, reduce inhibitory signaling, and promote long-term changes in synaptic function. Damage-associated molecular patterns released from injured tissues further activate immune pathways, thereby linking peripheral injury to central neuroinflammatory processes (25).

The acute-to-chronic transition: a dynamic process

Recent evidence suggests that the transition from acute to chronic pain is not abrupt but rather involves an intermediate stage, often referred to as early persistent pain, which typically develops within the first few weeks of surgery (29). During this phase, pain persists beyond the expected course of postoperative recovery and may reflect the emergence of central sensitization rather than ongoing peripheral nociceptive input alone. Importantly, clinical studies have shown that patients who develop early persistent pain are at increased risk of progressing to chronic postsurgical pain (37), suggesting that key neuroplastic changes may already be underway during this period (39).

At a broader level, the transition to chronic pain may also involve changes in higher-order brain regions related to pain processing and emotional regulation. In particular, alterations in the nucleus accumbens microcircuit—a key component of the mesolimbic system involved in reward and motivational processing—have been implicated in pain chronification. Similarly, synaptic plasticity in the anterior cingulate cortex, a region closely linked to the affective dimension of pain, may further contribute to pain persistence beyond tissue healing (39-42). These findings highlight early persistent pain as a critical therapeutic window for reassessment, pain phenotyping, and selective escalation of multidisciplinary care (Figure 1).

Figure 1.

From intercostal nerve injury to an integrated temporal and mechanism-based model of CPTS. The conventional model emphasizes intercostal nerve injury as the direct cause of persistent pain. The integrated model retains nerve injury as an important initiating event but places it within a longitudinal pathway shaped by tissue injury, peripheral sensitization, neuroinflammation, central sensitization, higher-order plasticity, psychological vulnerability, and the evolving postoperative pain trajectory. Regional analgesia is positioned within acute perioperative management; early persistent pain is a window for reassessment, pain phenotyping, psychological support, opioid stewardship, and selective transitional pain service referral. This is original artwork created for this review and is not reproduced or adapted from previously published material. CPTS, chronic pain after thoracic surgery; TPS, transitional pain service.

Risk factors and clinical risk stratification for CPTS

Risk factors for CPTS have been investigated extensively, but their reported effects vary considerably across studies. Rather than dividing predictors into fixed categories of “consistent” and “context-dependent” factors, it may be more clinically informative to interpret them according to reproducibility of association, independence after multivariable adjustment, modifiability, and potential utility for perioperative risk stratification. Thoracic-specific systematic reviews have identified numerous candidate prognostic factors, but only a limited number have shown reasonably reproducible associations across heterogeneous populations (16,17,43). Thus, risk prediction should be viewed as cumulative and dynamic rather than dependent on any single characteristic.

Acute postoperative pain and preoperative pain: the strongest clinical signals

Among perioperative variables, acute postoperative pain is one of the most repeatedly associated predictors of CPTS. Higher pain intensity during the first postoperative days has been associated with later persistent pain across prospective thoracic cohorts and systematic reviews (7,14,17,37,43-45). Qualitative features may also matter: acute neuropathic characteristics, including sensory disturbance and evoked pain, may identify patients in whom nerve-related mechanisms are already contributing to the postoperative pain phenotype (37,45).

However, this association should not be interpreted as evidence that acute pain alone causes CPTS. Severe acute pain may simultaneously reflect greater tissue injury, nerve injury, pre-existing pain sensitivity, psychological vulnerability, or inadequately controlled nociceptive input. Accordingly, acute postoperative pain is both a potentially modifiable treatment target and a dynamic marker of underlying vulnerability.

Preoperative pain is another relatively robust predictor. A recent thoracic-specific systematic review and meta-analysis reported that preoperative pain was associated with a substantially increased risk of chronic postsurgical pain after lung or pleural surgery (17). Unlike demographic factors, preoperative pain can also prompt further phenotyping before surgery, including identification of neuropathic features, ongoing analgesic use, previous chronic pain disorders, and functional interference.

Psychological vulnerability: risk marker and potentially modifiable target

Psychological factors represent an important component of perioperative pain vulnerability. Anxiety, depressive symptoms, pain catastrophizing, fear of pain, and negative expectations have been associated with acute and persistent postsurgical pain, although effect sizes and independent associations vary among thoracic cohorts (6,14,15,43,46-48). Importantly, these constructs should not be considered interchangeable. Procedure-specific fear, catastrophizing, and negative expectations are potentially modifiable perioperative states, whereas established anxiety or depressive disorders may represent more persistent background vulnerability requiring broader clinical management.

This distinction has practical implications. Psychological assessment need not require formal psychiatric evaluation in every patient; brief validated screening tools can be incorporated into preoperative assessment when clinically indicated. Patients with marked distress, catastrophizing, procedural fear, or pre-existing mental health conditions may benefit from enhanced education, expectation management, and, where available, targeted psychological support. Evidence from other major surgical populations, including the PSY-HEART randomized program, suggests that brief expectation-focused psychological interventions can improve aspects of postoperative recovery, although direct evidence for prevention of CPTS in thoracic surgery remains insufficient (49).

Patient-related and procedural modifiers

Female sex and younger age are frequently reported as candidate predictors of CPTS, but their associations are less stable than those of preoperative and postoperative pain. Meta-analyses restricted to VATS have identified associations with sex and age (16), whereas broader analyses of lung and pleural surgery have found insufficient evidence for sex and no consistent effect of age (17). These discrepancies illustrate an important limitation of individual risk-factor studies: associations may depend on surgical population, statistical adjustment, outcome definition, and correlations with other variables. Age and sex should therefore be considered markers of baseline susceptibility rather than independently actionable treatment targets.

Surgical factors are similarly heterogeneous. Compared with thoracotomy, VATS is associated with a lower overall risk of chronic pain in pooled thoracic data (17), supporting reduction of surgical trauma where clinically appropriate. However, within minimally invasive surgery, the predictive value of port number, extent of resection, operative duration, chest tube number, and duration of drainage is less consistent (7,16,17,43,50). A greater number of chest tubes and prolonged or painful drainage may increase ongoing intercostal and pleural nociceptive input, but these variables are also influenced by surgical complexity and postoperative complications. They should therefore be interpreted within the overall procedural context rather than as isolated causal determinants.

The role of perioperative opioid exposure is even less certain. High-dose short-acting opioids, particularly remifentanil, may increase postoperative pain sensitivity through opioid-induced hyperalgesia (OIH), but clinical associations with long-term CPTS remain inconsistent (51-56). Opioid exposure is consequently best regarded as a potentially modifiable component of the broader analgesic strategy rather than an established independent predictor of CPTS.

From individual predictors to cumulative risk

A central limitation of the available literature is that most predictors have been studied in isolation, despite CPTS arising from interacting biological, psychological, and procedural processes. A patient with pre-existing pain, high pain catastrophizing, an extensive thoracic procedure, and severe dynamic pain during the first postoperative days is likely to have a different risk trajectory from a patient with only one of these characteristics. Moreover, risk evolves after surgery: severe acute pain, neuropathic features, prolonged opioid requirements, delayed functional recovery, and pain persisting beyond the expected recovery trajectory provide additional information that cannot be captured by preoperative assessment alone.

Although several prediction models have recently been proposed for thoracic populations (57), external validation and evidence that model-guided interventions improve clinical outcomes remain limited. At present, therefore, structured clinical risk stratification is more defensible than reliance on a single numerical prediction score. Preoperative screening should identify baseline vulnerability, while repeated postoperative assessment should determine whether a patient is progressing along a higher-risk pain trajectory (Table 2).

Table 2. Clinical interpretation of major risk factors for chronic pain after thoracic surgery.

Risk domain	Thoracic evidence	Consistency/independence	Modifiability	Potential clinical use
Acute postoperative pain intensity	Repeatedly associated with CPTS in prospective cohorts and systematic reviews (7,14,17,37,43-45)	Relatively consistent, but may also reflect injury burden and baseline vulnerability	Partly modifiable	Assess resting and dynamic pain trajectories; reassess unexpectedly severe or poorly improving pain
Acute neuropathic features	Sensory disturbance, evoked pain, and neuropathic characteristics are associated with persistent phenotypes (37,45)	Moderate evidence; less frequently measured than intensity	Partly modifiable	Early sensory and neuropathic phenotyping; consider mechanism-directed treatment
Preoperative pain	Associated with increased risk after lung and pleural surgery (17,43,45)	Relatively robust across analyses	Baseline status is not immediately modifiable, but phenotype and treatment are	Characterize location, intensity, analgesic use, neuropathic features, and functional interference
Psychological vulnerability	Anxiety, depression, catastrophizing, fear, and negative expectations are associated with persistent pain in several studies (6,14,15,43,46,47)	Variable after adjustment; constructs and instruments differ	Potentially modifiable, especially fear, catastrophizing, and expectations	Brief screening; enhanced education and expectation management; targeted support when indicated
Female sex/younger age	Associations appear in some VATS analyses but are not consistently reproduced in broader thoracic meta-analyses (16,17)	Inconsistent	No	Background susceptibility markers; should not independently determine treatment
Surgical approach	VATS generally carries lower risk than thoracotomy; evidence distinguishing uniportal, multiportal, and robotic approaches remains limited (7,10,11,16-19)	Moderate-to-high for VATS versus thoracotomy; limited for newer comparisons	Partly	Inform expected pain burden and procedure-specific analgesic planning
Operative burden	Longer duration or greater procedural burden has been associated with CPTS (17,43)	Variable; may reflect complexity	Limited	Contextual marker rather than an isolated target
Chest tubes/drainage	Number, duration, and painful drainage have been associated with CPTS in selected studies (16,17,43)	Heterogeneous and confounded by surgical complexity	Potentially modifiable when clinically appropriate	Minimize unnecessary drainage and optimize positioning and removal timing
Perioperative opioid exposure	High-dose remifentanil can increase acute pain sensitivity; direct associations with CPTS remain inconsistent (51-55,58,59)	Low/inconsistent for CPTS	Modifiable	Avoid unnecessary high-dose exposure; use opioid-sparing multimodal care
Early persistent pain trajectory	Pain persisting during the weeks after surgery identifies a higher-risk trajectory (37,39,40)	Emerging but clinically compelling	Potentially modifiable	Structured post-discharge surveillance and early escalation/TPS referral

Evidence descriptors are qualitative narrative appraisals and should not be interpreted as formal GRADE ratings. CPTS, chronic pain after thoracic surgery; TPS, transitional pain service; VATS, video-assisted thoracic surgery.

Prevention and management strategies

Given the multifactorial mechanisms underlying CPTS development, preventive strategies can be broadly categorized into pharmacological, regional, neuromodulatory, and integrative approaches. However, the effectiveness of these strategies varies depending on the extent to which they address the key mechanisms involved in pain chronification.

Systemic pharmacological analgesia: beyond opioid-based strategies

Systemic pharmacological analgesia remains an essential component of perioperative pain management in thoracic surgery (60). Unlike regional techniques, which primarily reduce peripheral nociceptive input, systemic agents exert broader effects on both peripheral and central pain pathways. However, their role in preventing CPTS remains complex and incompletely defined.

Opioids: necessary but potentially detrimental

Opioids remain a mainstay of perioperative analgesia due to their potent efficacy in acute pain control (58). However, increasing evidence suggests that excessive opioid exposure may, in some settings, contribute to increased postoperative pain sensitivity and potentially influence long-term pain outcomes. Mechanistically, opioids may induce OIH through the activation of pronociceptive pathways, including NMDA receptor facilitation and descending pain facilitation (54). Clinically, high intraoperative opioid doses, particularly high-dose remifentanil administration, have been associated with increased postoperative pain sensitivity and greater analgesic requirements (55). These findings highlight the dual role of opioids as both analgesics and potential modulators of long-term pain outcomes, emphasizing the need for opioid-sparing strategies. Emerging agents such as oliceridine, a biased µ-opioid receptor agonist, may offer effective analgesia with fewer adverse effects; however, their effects on postoperative hyperalgesia and the development of chronic pain remain unclear.

NMDA receptor antagonists and central sensitization

NMDA receptor activation plays a central role in the development of central sensitization. Accordingly, NMDA antagonists such as ketamine have been extensively studied for their potential to prevent chronic pain development. Experimental and clinical evidence suggests that ketamine can attenuate OIH, reduce acute postoperative pain, and decrease opioid consumption (61). However, its effects on long-term pain outcomes remain inconsistent. While some studies have reported a reduction in the incidence of chronic postsurgical pain, others have failed to demonstrate significant benefit (59,62). These discrepancies likely reflect differences in dosing, timing of administration, patient selection, and the broader multimodal analgesic context, as well as the multifactorial nature of CPTS (59,61,62).

Anti-inflammatory strategies and neuroinflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors reduce peripheral inflammation and nociceptive input by inhibiting prostaglandin synthesis and attenuating nociceptor sensitization. In addition, emerging evidence suggests that targeting inflammatory pathways may attenuate central sensitization and thereby reduce the risk of chronic pain development (63,64). However, although perioperative anti-inflammatory strategies have demonstrated efficacy in reducing acute postoperative pain and opioid consumption (65), clinical data specifically linking their use with a reduced incidence of CPTS remain limited.

Gabapentinoids and neuropathic pain modulation

Gabapentinoids, including gabapentin and pregabalin, are widely used in the management of neuropathic pain. Their mechanism of action involves the inhibition of voltage-gated calcium channels, thereby reducing the release of excitatory neurotransmitters. Although these agents have shown efficacy in reducing acute postoperative pain and opioid consumption, their role in preventing chronic pain remains controversial. Some trials have reported a reduced incidence of persistent pain, whereas others have reported minimal benefit (66,67). Moreover, concerns regarding sedation, dizziness, and respiratory depression limit their routine application in all patient populations.

α2-adrenergic agonists and central modulation

α2-adrenergic agonists, particularly dexmedetomidine, are increasingly used as adjuncts in perioperative analgesia due to their sedative and opioid-sparing properties. These agents exert their effects through central α2-receptor activation, enhancing descending inhibitory pathways and reducing sympathetic outflow (68). Clinical studies have demonstrated that dexmedetomidine can reduce acute postoperative pain intensity and opioid requirements in thoracic and other surgical settings (69); however, evidence supporting its role in CPTS prevention remains limited. Current evidence does not support a consistent reduction in the incidence of CPTS, suggesting that its effects are likely confined to the modulation of early postoperative pain rather than long-term pain outcomes.

Regional anesthesia: from neuraxial to fascial plane approaches

Regional anesthesia remains a cornerstone of perioperative analgesia in thoracic surgery (60,70). Thoracic epidural analgesia (TEA) provides excellent bilateral analgesia and has long been considered the reference standard for thoracic surgery; however, its use is limited by the technical expertise required for epidural catheter placement, the risk of hypotension, and rare but serious complications such as total spinal anesthesia and epidural hematoma (71). Thoracic paravertebral block (TPVB) offers a unilateral alternative with a more favorable hemodynamic profile and comparable analgesic efficacy in many settings (72). In recent years, fascial plane blocks have emerged as attractive alternatives, particularly in minimally invasive surgery. These techniques include the erector spinae plane block (ESPB), serratus anterior plane block (SAPB), and intercostal plane block (73). Their technical simplicity, favorable safety profile, and reproducibility have contributed to their increasing adoption in clinical practice (74,75). However, their mechanisms differ fundamentally from those of TEA and TPVB. Fascial plane blocks rely on the spread of local anesthetic along tissue planes, resulting in indirect and often variable blockade of intercostal nerve transmission. As a result, their analgesic effects may be less dense and less predictable.

From a chronic pain perspective, current evidence remains limited and inconsistent. Although regional analgesia techniques, including TEA and TPVB, provide effective acute postoperative analgesia, their ability to prevent CPTS has not been clearly demonstrated. Systematic reviews and meta-analyses indicate that while these techniques improve early pain control, they do not consistently reduce the incidence of chronic post-thoracotomy pain (76,77). Similarly, comparative studies have reported no significant differences in long-term pain outcomes between different regional techniques (78,79).

Emerging fascial plane blocks, such as ESPB and SAPB, further improve the safety and feasibility of regional analgesia. However, their role in chronic pain prevention remains even less well defined. This may reflect incomplete blockade of deep nociceptive pathways, particularly those associated with intercostal nerve injury, as well as the relatively short duration of action of single-injection techniques. Consequently, while regional analgesia is essential for acute pain management, its influence on long-term pain modulation appears limited. Importantly, these observations suggest that the depth, duration, and continuity of neural blockade, rather than the specific anatomical approach alone, may represent critical determinants of long-term pain outcomes.

Continuous wound infiltration represents a simple, surgeon-delivered alternative that has been incorporated into multimodal analgesic strategies (60). Although it provides effective acute analgesia with opioid-sparing effects (80), its efficacy is generally inferior to that of neuraxial and paravertebral techniques, and current evidence does not support a reduction in chronic postsurgical pain (81).

Cryoanalgesia has re-emerged as a technique for postoperative pain control in thoracic surgery, involving targeted freezing of intercostal nerves to achieve prolonged sensory blockade. By inducing reversible axonal degeneration, cryoanalgesia can provide extended analgesia lasting several weeks to months. Clinical studies have reported reduced postoperative opioid consumption and satisfactory acute pain control following thoracic surgery (82,83); however, its effects on chronic pain outcomes remain controversial. In one randomized study, intercostal nerve cryoanalgesia was associated with a higher incidence of allodynia-like pain and greater chronic pain severity than TEA during long-term follow-up, raising concerns regarding potential neuropathic sequelae (83).

Neuromodulation strategies: emerging adjuncts

Neuromodulation strategies have emerged as adjunctive approaches for perioperative pain management, targeting both peripheral and central mechanisms involved in pain processing. Unlike pharmacological and regional techniques, these approaches aim to modulate neural activity and pain perception without direct tissue blockade.

Noninvasive neuromodulation

Transcutaneous electrical nerve stimulation (TENS) is one of the most widely used noninvasive neuromodulation techniques. It is thought to exert analgesic effects through the activation of large-diameter afferent fibers and the engagement of descending inhibitory pathways (84,85). In thoracic surgery, TENS has been associated with modest reductions in acute postoperative pain intensity and opioid consumption; however, its role in chronic pain prevention remains uncertain due to limited and heterogeneous evidence (86).

A related modality, transcutaneous electrical acupoint stimulation (TEAS), applies similar electrical stimulation to acupuncture points and has demonstrated opioid-sparing and analgesic effects in perioperative settings, including thoracic procedures (87). However, evidence regarding the effects of TEAS on long-term outcomes, including CPTS, remains insufficient (88).

Repetitive transcranial magnetic stimulation (rTMS) represents another noninvasive approach targeting cortical pain networks, particularly regions involved in pain modulation such as the motor cortex and prefrontal areas. Although rTMS has shown efficacy in certain chronic pain conditions, its perioperative application remains exploratory, and evidence in thoracic surgery is currently lacking (89).

Invasive neuromodulation

Spinal cord stimulation (SCS) is an established therapy for the management of refractory neuropathic pain. It modulates dorsal column pathways and alters central pain processing. Although SCS is not used in the immediate perioperative setting, it may have a role in the management of severe, refractory CPTS, particularly in patients with dominant neuropathic features (90).

Mechanistic relevance and limitations

Overall, neuromodulation represents a mechanistically attractive approach for pain modulation; however, current clinical evidence primarily supports its use as an adjunctive therapy for acute postoperative pain and for the management of established chronic neuropathic pain (84-90). However, evidence demonstrating its effectiveness in preventing CPTS remains limited.

Multimodal and bundled perioperative care: integration rather than accumulation

Multimodal analgesia is strongly recommended within enhanced recovery pathways for thoracic surgery and remains the appropriate foundation of perioperative pain management (60,70). Its established advantages include improved acute pain control, reduced opioid requirements, and facilitation of coughing, mobilization, and pulmonary recovery. Enhanced recovery after thoracic surgery (ERATS) programs further combine analgesia with preoperative preparation, minimally invasive surgical practice, early mobilization, pulmonary rehabilitation, nutrition, and standardized postoperative care; systematic reviews generally demonstrate reductions in hospital stay and postoperative complications (70,91).

However, multimodal analgesia should not be equated with simply adding multiple analgesic interventions. The relevant question for CPTS prevention is whether the selected components collectively address the dominant mechanisms and risk trajectory of a given patient. Current evidence does not demonstrate that a greater number of perioperative analgesic modalities necessarily produces a proportional reduction in chronic pain. Ketamine, gabapentinoids, regional techniques, anti-inflammatory agents, and neuromodulatory approaches all provide benefits in selected settings, yet their effects on CPTS are inconsistent (59,61-67,76-79,92,93).

Several methodological and biological factors probably contribute to these discrepant findings. First, studies differ substantially in surgical procedures, baseline patient risk, intervention dose and duration, concomitant analgesic regimens, chronic pain definitions, and follow-up intervals. Second, most interventions are initiated around surgery and discontinued within hours or days, whereas peripheral sensitization, neuroimmune activation, central plasticity, psychological distress, and activity-related nociceptive input may continue for weeks. Thus, an intervention may successfully reduce early pain without substantially altering the subsequent pain trajectory. Third, standardized regimens may not address the dominant mechanism in every patient; for example, intensified conventional analgesia may have limited effect on prominent neuropathic or psychological components.

These considerations favor a shift from fixed multimodal protocols toward bundled and adaptive perioperative care. Standard ERATS-based care should provide procedure-specific, opioid-sparing multimodal analgesia and appropriate regional techniques for most patients. Additional components should then be selected according to individual risk and postoperative trajectory rather than routinely applied to all patients. This approach preserves the benefits of standardized enhanced recovery while allowing escalation for patients with severe dynamic pain, neuropathic features, psychological vulnerability, prolonged opioid requirements, or early persistent pain.

Importantly, current ERATS evidence primarily demonstrates improvements in short-term recovery outcomes; direct evidence that ERATS bundles prevent CPTS remains limited (70,91). Bundled care is therefore biologically and clinically plausible but should not yet be presented as an established CPTS-prevention strategy. Future trials should evaluate whether risk-adapted ERATS pathways can alter long-term pain trajectories rather than focusing exclusively on pain scores, opioid consumption, and length of hospital stay.

Clinical translation: a risk-stratified perioperative pathway

The available evidence does not currently support a single intervention capable of reliably preventing CPTS. A more practical strategy is therefore to combine standard procedure-specific care with longitudinal risk assessment and selective escalation of treatment.

Preoperative phase: identify vulnerability

Risk assessment can begin during routine anesthetic or surgical evaluation. Clinically relevant domains include pre-existing pain and analgesic use, chronic opioid exposure, previous chronic pain disorders, psychological distress or marked procedural fear, anticipated surgical approach and complexity, and other factors associated with difficult postoperative recovery. Preoperative pain should be characterized rather than simply recorded as present or absent, with attention to location, intensity, neuropathic features, and functional interference.

Patients with substantial psychological vulnerability may benefit from enhanced education and expectation management. Brief psychological interventions targeting maladaptive expectations have improved recovery outcomes in cardiac surgical populations, providing proof of concept that perioperative psychological factors can be modified (49). However, extrapolation to CPTS prevention should remain cautious until thoracic-specific trials are available.

Perioperative phase: optimize dynamic pain control without unnecessary treatment burden

For most patients, the foundation should remain guideline-concordant ERATS care incorporating multimodal systemic analgesia, opioid minimization, and an appropriate regional technique based on surgical approach, institutional expertise, patient comorbidity, and expected pain burden (60,70). The aim should extend beyond resting pain scores to adequate analgesia during coughing, deep breathing, and mobilization, because these activities repeatedly activate the thoracic surgical site.

Patients with a high preoperative risk profile or unexpectedly severe early postoperative pain should prompt reassessment rather than automatic escalation of opioid therapy alone. Potential contributors—including inadequate regional analgesia, neuropathic features, surgical complications, anxiety, sleep disturbance, and pre-existing opioid tolerance—should be considered, allowing treatment to be adapted to the dominant phenotype.

Post-discharge phase: identify early persistent pain

Hospital discharge should not be regarded as the end of CPTS prevention. Patients with severe acute pain, prolonged opioid requirements, marked neuropathic features, or high psychological vulnerability may benefit from structured follow-up during the first postoperative weeks. Pain that fails to improve along the expected recovery trajectory should trigger reassessment of pain phenotype, functional recovery, analgesic use, sleep, mood, and return to normal activity.

This period is particularly relevant to the concept of early persistent pain, which may provide a practical bridge between acute postoperative care and conventional chronic pain management. Rather than waiting until the 3-month diagnostic threshold for CPTS has been reached, persistent or worsening pain during the first postoperative weeks may justify earlier multidisciplinary intervention.

Role of a transitional pain service (TPS)

A TPS provides a potential organizational model for this longitudinal approach. Such services bridge acute inpatient pain management and outpatient follow-up and commonly combine pain-physician assessment, opioid stewardship, psychological or behavioral support, and rehabilitation. Available studies suggest that TPS programs can facilitate postoperative opioid reduction and may improve pain interference and functional recovery, although evidence that they specifically prevent CPTS remains limited and is derived predominantly from non-thoracic populations (48).

Accordingly, universal referral of all thoracic surgical patients to a TPS would neither be practical nor evidence based. A more feasible model is selective referral of higher-risk patients, including those with pre-existing chronic pain or opioid use, severe or neuropathic acute postoperative pain, persistent opioid requirements, substantial psychological vulnerability, or pain that fails to improve during the early postoperative weeks. Where a formal TPS is unavailable, similar principles can be implemented through coordinated follow-up involving anesthesiology/pain medicine, thoracic surgery, primary care, rehabilitation, and psychological services.

Taken together, this framework reframes CPTS prevention as a longitudinal process rather than a single perioperative intervention: risk is identified before surgery, modified where possible during perioperative care, reassessed through postoperative pain trajectories, and escalated when early persistent pain emerges. The principal preventive and management strategies for CPTS, together with their mechanistic targets, current level of evidence, major limitations, and proposed clinical roles, are summarized in Table 3.

Table 3. Preventive and management strategies for CPTS: evidence, limitations, and proposed clinical role.

Strategy	Principal target	Acute benefit	Evidence for CPTS prevention	Major limitations	Proposed clinical role
NSAIDs/COX-2 inhibitors	Peripheral inflammation and nociceptor sensitization	Established (60,70)	Limited	Few trials designed around chronic pain outcomes	Standard opioid-sparing component unless contraindicated
Opioids	μ-opioid receptor analgesia	Established	No preventive benefit established; high exposure may increase pain sensitivity (51-55,58,59)	OIH, tolerance, adverse effects, and confounding by indication	Rescue or individualized analgesia rather than a sole preventive strategy
Ketamine	NMDA-mediated central sensitization	Moderate-to-strong (61,62)	Conflicting	Heterogeneous dose, timing, populations, follow-up, and co-analgesia	Selected high-risk or opioid-tolerant patients; not routine solely for CPTS prevention
Gabapentinoids	α2δ calcium-channel modulation/neuropathic signaling	Modest and context dependent	Conflicting/limited (66,67)	Sedation, dizziness, respiratory concerns, and heterogeneous trials	Selective use when neuropathic features or another indication outweigh harms
α2-adrenergic agonists	Descending inhibition and opioid sparing	Moderate (68,69)	Insufficient	Long-term CPTS outcomes rarely evaluated	Adjunct within multimodal analgesia; not established for CPTS prevention
TEA/TPVB	Dense interruption of thoracic nociceptive input	Established	Inconsistent (72,76-79)	Technique, duration, comparator, and follow-up vary	Procedure- and patient-specific regional analgesia, primarily to optimize acute recovery
Fascial plane blocks (ESPB/SAPB)	Indirect intercostal nociceptive blockade	Moderate (73-75)	Insufficient	Variable spread and duration; few long-term trials	Alternatives when neuraxial or TPVB techniques are undesirable or impractical
Continuous wound infiltration	Local incisional nociceptive input	Moderate (80,81)	Insufficient	Less dense blockade and limited chronic outcome data	Simple adjunct where appropriate
Cryoanalgesia	Prolonged intercostal nerve conduction interruption	Moderate for selected procedures (82,83)	Uncertain	Heterogeneous techniques and possible neuropathic sequelae	Selected use; long-term benefit-risk balance requires clarification
TENS/TEAS	Peripheral sensory input and descending modulation	Modest (84-88)	Insufficient	Small studies, heterogeneous protocols, and little long-term follow-up	Low-risk adjunct for acute pain and opioid sparing
Education/psychological intervention	Expectations, fear, catastrophizing, and coping	Emerging evidence for recovery outcomes (49)	Promising, but thoracic-specific evidence is insufficient	Most interventional evidence comes from non-thoracic surgery	Target patients with psychological vulnerability and integrate with routine education
ERATS bundle	Multiple biological and recovery domains	Strong for recovery, length of stay, and selected complications (70,91)	Direct evidence insufficient	Variable protocol composition; chronic pain rarely a primary outcome	Standard platform on which risk-adapted CPTS prevention can be built
Transitional pain service	Longitudinal pain, opioid, behavioral, and functional management	Not primarily an acute intervention	Promising but low-certainty (48,57)	Mostly observational or non-thoracic evidence; resource intensive	Selective referral for high-risk patients or early persistent pain

Evidence descriptors are qualitative narrative summaries rather than formal evidence grades. COX-2, cyclooxygenase-2; CPTS, chronic pain after thoracic surgery; ERATS, enhanced recovery after thoracic surgery; ESPB, erector spinae plane block; NMDA, N-methyl-D-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs; OIH, opioid-induced hyperalgesia; SAPB, serratus anterior plane block; TEA, thoracic epidural analgesia; TEAS, transcutaneous electrical acupoint stimulation; TENS, transcutaneous electrical nerve stimulation; TPVB, thoracic paravertebral block.

Conclusions

CPTS remains common despite less invasive thoracic surgery and increasingly sophisticated perioperative analgesia. The available evidence suggests that this persistence cannot be explained by intercostal nerve injury or inadequate acute analgesia alone. Rather, CPTS develops through dynamic interactions among peripheral injury, neuroimmune activation, central sensitization, psychological vulnerability, and the postoperative pain trajectory.

The major clinical implication is therefore not to identify a single “best” analgesic technique, but to align the intensity, mechanism, and duration of intervention with individual risk over time. Procedure-specific multimodal and regional analgesia should remain the foundation of routine thoracic perioperative care, while patients with pre-existing pain, psychological vulnerability, severe or neuropathic acute pain, prolonged opioid requirements, or early persistent pain may require more intensive and longitudinal management.

Several priorities should guide future research. First, thoracic-specific risk prediction models require external validation and testing within intervention studies. Second, chronic pain outcomes and pain phenotypes should be measured using standardized definitions and sufficiently long follow-up. Third, prospective studies should characterize the early persistent pain phase and determine whether intervention during this period can alter pain chronification. Finally, future trials should evaluate risk-stratified, mechanism-informed care pathways, including psychological interventions and TPS, rather than assessing individual analgesic modalities in isolation. Such an approach may provide a more realistic pathway toward reducing the long-term burden of CPTS.

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