The anesthesiologist's role in preventing chronic post-surgical pain and opioid use through neurobiological programming: a mini review

1 Introduction

The trajectory from acute surgical trauma to the development of CPSP and postoperative COU is increasingly predictable and mechanistically understood. The development of chronic pain following a surgery is a widespread phenomenon, contributing significantly to patient suffering, functional limitations, and psychological trauma (1–3). While incidence varies considerably by the type of surgery, high-risk surgeries like thoracotomies and breast surgeries exhibit substantial rates of CPSP (3). This persistence of pain beyond the standard healing window represents a significant societal burden. The risk of developing COU following surgery is substantial; in opioid-naïve patients, COU incidence ranges from approximately 3.9%–14%, with some studies showing approximately 10% persistence in older populations (4). This significant iatrogenic burden, driven by the introduction of opioids during perioperative pain management, exacerbates the existing public health crisis.

To effectively prevent these long-term morbidities, a precise definition of each is required: CPSP: Defined as pain that persists for a minimum of three months following surgery, is localized to the surgical field or the nerve innervation territory within that field and cannot be attributed to pre-existing conditions or new causes (2, 3). COU: Defined in administrative claims data as prolonged utilization, specifically requiring the patient to have filled ten or more prescriptions or obtained more than 120 days’ supply of an opioid during the postsurgical year, critically excluding the immediate first 90 postoperative days to differentiate expected acute pain management from pathological chronicity (5).

Preoperative psychosocial factors, including anxiety, depression, and pain catastrophizing, are validated and routinely utilized markers for risk stratification (2, 5, 6). The underlying biological mechanisms linking surgical insult to chronicity are multifactorial and involve both peripheral and central processes. Key pathways include sustained neuroinflammation driven by central cytokine release (7), enduring molecular programming via epigenetic changes (8, 9), and the perturbation of the gut-brain axis through anesthetic- or opioid-induced dysbiosis (10, 11). The perioperative period serves as a unique window of maximal vulnerability and therapeutic opportunity for prevention of CPSP and COU. This is the precise time when intense nociceptive input from surgical trauma intersects with widespread systemic and central neuroinflammatory signaling, coinciding with the administration of potent pharmacological agents, including anesthetics and opioids (7, 12). Anesthesiologists are uniquely positioned to leverage mitigation strategies focused on neural blockade and targeted pharmacology to potentially stop these pathways (13, 14). Systemic strategies also include the administration of non-opioid adjuncts, such as intravenous lidocaine, which reduces peripheral and central sensitization (CS) (15–17).

The choices made by the anesthesiologist regarding technique and adjuncts to mitigate pain during the perioperative period can influence the level of Central Sensitization (CS) and the processes that can chemically program the nervous system for long-term pain (8, 18). Therefore, the anesthetic goals should extend beyond surgical safety, anesthesia, and amnesia; they must also consider how the technique serves as a primary determinant of long-term pain and opioid outcomes (6, 19).

2 Methods

A comprehensive narrative literature review was conducted across PubMed and Google Scholar to identify relevant articles on chronic post-surgical pain and chronic opioid use, focusing on risk factors and mitigation strategies studied over the last 25 years (February 2000 to December 2025). The search strategy combined keywords including “chronic post-surgical pain,” “CPSP,” “chronic opioid use,” “COU,” “risk factors,” “perioperative management,” “precision medicine,” “neuroinflammation,” “epigenetics,” “gut-brain axis”, “gut microbiome modulation”, “Anesthesia adjuvants” “biomarkers”, and “multimodal analgesia.” This review adheres to the principles of narrative synthesis, prioritizing key randomized controlled trials, systematic reviews, and mechanistic preclinical studies to synthesize current understanding.

3 Preoperative predictors and mechanistic pathways of chronicity

The synthesis of the included studies confirms that the risk for developing CPSP and COU is predictable, driven by converging patient-specific neurobiological and iatrogenic factors.

3.1 Preoperative risk predictors

The risk for CPSP and prolonged COU is strongly associated with pre-existing patient characteristics (2, 5, 6). This notion suggests that a structured approach to preoperative risk screening is needed, transforming the anesthetic consultation from a checklist review into a more comprehensive risk-mitigation approach (Table 1) (3, 19).

Table 1. Summarizes the key preoperative risk factors and stratification for CPSP and COU.

3.1.1 Psychosocial and pain phenotypic

Anxiety, depression, sleep disturbance, and pain catastrophizing (an exaggerated negative mindset toward pain that involves magnifying its severity) (2) are consistently identified as robust predictors of chronic pain (2, 4, 5). These preoperative psychological factors, often termed the “Negative Affect Phenotype,” are not merely symptoms but quantifiable markers reflecting underlying neurobiology (7, 8). The history of pre-existing chronic pain and preoperative opioid use are also major risk factors, significantly increasing the likelihood of persistent opioid consumption and difficulty in weaning postoperatively (4, 5).

3.1.2 Biological predictors: genomics, hyperalgesia, and biomarkers

Precision medicine is an emerging approach that takes into account individual variability in genes, environment, and lifestyle. In anesthesia, epigenetic heritable changes in gene expression not involving alterations to the underlying DNA sequence offer critical insight into how patients may differentially respond to anesthetic agents and pain management strategies by influencing the expression of genes encoding drug-metabolizing enzymes and opioid receptors (20). This shift towards personalization is heavily reliant on ‘omics’ data (genomics, epigenetics, etc.), which reveal inter-individual variability in drug response and perioperative risk (20). For instance, genetic polymorphisms in cytochrome P450 (CYP) enzymes, such as CYP2B6 and CYP3A4/3A5, significantly influence the metabolism of commonly used agents, including propofol, ketamine, and midazolam, leading to variable efficacy and duration of action.

Similarly, variants in the mu-opioid receptor gene OPRM1, such as A118G, are critical determinants of opioid analgesic requirements and the risk of postoperative nausea and vomiting (PONV) (9, 21).

Hyperalgesia, defined as increased sensitivity to experimental pain stimuli, is an independent risk factor for CPSP during procedures such as total knee arthroplasty and herniotomy (3, 7). Studies have shown that precision medicine can use molecular biomarkers (e.g., circulating cytokines, IL-1β, TNF-α), Matrix Metalloproteases (MMPs), and genetic polymorphisms (e.g., the μ-opioid receptor gene OPRM1 and catechol-O-methyltransferase COMT gene variants) to predict pain response and guide opioid-sparing protocols (20).

The development of integrated biosignatures, more robust predictive models, integrates markers across genetic, molecular, and neurophysiological domains (22).

3.1.3 Biomarkers

Recent evidence has validated sensorimotor cortical biomarkers, such as Peak Alpha Frequency (PAF) and Corticomotor Excitability (CME), which objectively map CNS changes indicative of CS and predict prolonged pain sensitivity. Large-scale initiatives, such as the Acute to Chronic Pain Signatures (A2CPS) program, are working to validate these multimodal biosignatures to accurately identify high-risk individuals before surgery (22). These observations suggest that individuals who rate experimental pain stimuli as being of increased intensity possess an underlying altered pain sensitivity that predisposes them to chronic postoperative syndromes (7).

3.1.4 Clinical integration

Multivariable models incorporating both precision medicine with biomarkers, along with the psychosocial predictors of pain, show exceptionally high predictive accuracy for patients at risk for prolonged opioid use. This suggests that integration of validated psychological screening should be standardized into preoperative anesthetic consultation (5, 13). This stratification is the foundation for the targeted Transitional Pain Service (TPS) intervention, which has demonstrated efficacy in managing high-risk patients (Table 1) (2, 19).

3.2 Core mechanistic pathways of chronicity

Surgical trauma can initiate complex neurobiological and epigenetic reprogramming, stressing the rationale for mechanism-targeted interventions during the perioperative period to prevent CPSP and COU.

3.2.1 Central sensitization (CS) and neuroinflammation

Surgical injury can induce CS, a heightened pain state driven by sustained neuroinflammation characterized by increased central cytokines and chemokines (7, 12). This perpetual inflammatory state, mediated by glial cells (microglia and astrocytes), promotes hyperalgesia and allodynia (pain evoked by non-noxious stimuli), potentially promoting chronic widespread pain (7, 8).

3.2.2 Epigenetics reprogramming

Anesthetics and opioids themselves are capable of inducing prolonged epigenetic changes (9, 12). Preclinical data suggest that exposure to general anesthesia and surgery can lead to altered DNA methylation in genes regulating synaptic plasticity (e.g., Arc and JunB), with some changes persisting for over a year (9, 12). This suggests viewing the intraoperative period as a critical window of neuroplastic vulnerability requiring mechanism-based protective interventions to prevent altering the epigenetic status of the host's tissue post-surgery (8, 9).

3.2.3 The gut-brain axis

General anesthetics and opioids are known to disrupt gut microbial homeostasis, leading to dysbiosis that has been implicated in the development of opioid tolerance and chronic neuropathic or visceral pain through the gut-brain axis (9, 11, 23). Preclinical studies demonstrate that microbial metabolites, particularly Short-Chain Fatty Acids (SCFAs), can modulate neuroinflammatory pathways, highlighting the gut microbiome as a promising therapeutic target for preventing CPSP and COU (10, 23). Proposed mechanisms include immunomodulation and microglia activation triggered by altered levels of circulating bacterial metabolites, such as lipopolysaccharide. Collectively, these findings underscore the pivotal role of the gut microbiota in shaping the central nervous system's inflammatory status (Table 2) (10, 11).

Table 2. Outlines the proposed mechanisms and emerging interventions utilizing the gut microbiome and its role in pain.

4 Evidence-based perioperative interventions: a mechanism-targeted approach

Anesthesiologists can interrupt the trajectory to chronicity by implementing targeted analgesic strategies that directly address the identified neurobiological pathways (Table 3).

Table 3. Perioperative anesthetic modalities on long-term outcomes.

A comprehensive list of the literature used in this mini review can be found in Table 4.

Table 4. Results.

4.1 Pharmacological strategies to modulate central sensitization

The administration of intravenous adjuncts aims to inhibit receptor activation across distinct pain pathways:

• Lidocaine remains an important non-opioid analgesic, attenuating peripheral nociception and central sensitization through sodium channel inhibition, while also exerting anti- inflammatory effects (15–17). Clinical reports indicate that perioperative use can reduce postoperative neuropathic pain at three months (15).
• Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, prevents CS and reduces acute postoperative opioid consumption (18).
• Magnesium sulfate, a non-competitive NMDA receptor blocker, provides acute antinociception and reduces opioid use for up to 24 h (18)
• Dexmedetomidine, an alpha-2 agonist, highly effective opioid-sparing agent, reducing postoperative pain intensity and overall opioid requirements (24). Reduced time to extubation, decreased intensive care unit (ICU) length of stay, and indirectly diminished the cumulative window of high-dose opioid exposure and dependency risk (24).
• Dexamethasone, an anti-inflammatory glucocorticoid and sympatholytic that prevents chronicity. It also reduces acute opioid consumption (e.g., a 34% relative decrease on Postoperative Day 1) and pain reduction (18).
• Non-steroidal anti-inflammatory drugs (NSAIDs), strong evidence supports optimizing anti- inflammatory combinations plus dexamethasone to provide a reduction in postoperative opioid consumption (mean reduction ≈ −29.5 OMEs) (18).
• Esmolol, a short-acting β1-adrenergic antagonist, is utilized for its sympatholytic and peripheral analgesic properties, reducing intraoperative opioid use and immediate postoperative pain scores (18). Its ability to dampen the sympathetic nervous system and modulate systemic inflammation provides a compelling mechanistic rationale for its potential role in mitigating central neuroinflammation and preventing CPSP (7, 18).

4.2 Regional anesthesia and neural blockade

Regional techniques that block nociceptive transmission are highly effective in reducing postoperative pain. Literature reports that epidural anesthesia and paravertebral blocks significantly reduced the incidence of CPSP at six months following high-risk procedures such as thoracotomy and breast surgery (2, 3). This benefit is attributed to suppression of high- intensity nociceptive signaling before it reaches the central nervous system (7). Evidence also indicates that routine use of continuous catheter-based peripheral nerve blocks (CPNBs) offers no clear advantage over single-shot blocks for general postoperative analgesia and is associated with higher complication rates. Accordingly, CPNBs should be reserved for individualized use in high-risk or opioid-tolerant patients (13, 14, 24).

4.3 Anesthetic choice and epigenetic modulation

The intraoperative choice of anesthetic technique remains a key debate for preventing long-term sequelae.

4.3.1 Total intravenous anesthesia (TIVA)

TIVA, typically using propofol, has been explored as a potentially safer option for high- risk patients. The hypothesis is that volatile agents may trigger neuroinflammation, leading to greater epigenetic changes, while propofol-based TIVA may offer a neuroprotective or anti- inflammatory advantage (8, 12, 25, 26). Further high-quality evidence is needed, but this mechanism provides a strong rationale for TIVA use in highly stratified patients.

4.3.2 Targeting the gut-brain axis

Emerging preclinical data exploring the comparative effects of volatile agents vs. TIVA on inflammatory signaling also suggest a role for modulating chronicity via the gut microbiome using targeted probiotics (23, 27–29). This remains a speculative area for human application but highlights future avenues for intervention.

4.3.3 Transitional pain service (TPS)

The TPS model represents the optimal multidisciplinary care strategy for high-risk patients identified through preoperative screening (2, 19). These services provide coordinated care from the preoperative period through the acute postoperative phase and into the recovery window, managing high-risk factors like preoperative opioid use and severe anxiety, and ensuring a safe opioid taper plan.

4.4 Gabapentinoid dilemma

Gabapentinoids (gabapentin, pregabalin) modulate voltage-gated calcium channels, reducing excitatory neurotransmitter release and attenuating central sensitization (30). It has been reported that their perioperative use decreases acute postoperative pain and opioid consumption; however, evidence for preventing CPSP remains inconsistent (30). Systematic reviews demonstrate limited long-term analgesic efficacy, with no consistent prevention of chronic pain (30). Current recommendations therefore advise restricting gabapentinoid use to carefully selected patients, particularly those at high risk for opioid tolerance or neuropathic pain, rather than broad prophylactic administration.

5 Linical translation

Effective prevention of CPSP and COU requires a multidisciplinary perioperative pain management approach rather than reliance on a single anesthetic technique. Four key pillars support this paradigm:

• (I) Pre-habilitation & Screening: Early identification and management of psychosocial risk factors and hyperalgesia through TPS (2, 19).
• (II) Surgical Optimization: Minimizing tissue trauma, shortening operative time, and preventing iatrogenic nerve injury (2, 3).
• (III) Mechanism-Based Anesthesia: Strategic use of regional techniques and careful selection between TIVA and volatile agents, guided by concerns about neuroinflammation and epigenetic effects (9, 12–14).
• (IV) Targeted Pharmacological Intervention: Using evidence-based non-opioid adjuncts (lidocaine, ketamine, dexmedetomidine, NSAIDs, esmolol) while avoiding routine prophylactic gabapentinoid use due to limited efficacy (15, 30).

6 Limitations and controversies

Although mechanistic evidence on neuroinflammation and epigenetics is compelling, the clinical impact of anesthetic choice on long-term outcomes remains uncertain. Confounding factors such as heterogeneous surgical models, patient variability, and difficulty separating anesthetic effects from surgical influences limit definitive conclusions. Additionally, promising preclinical findings on epigenetics and the gut microbiome require rigorous clinical validation before translation into routine practice.

7 Conclusions and future directions

The prevention of CPSP and COU in surgical patients is achievable through the application of personalized medicine that accounts for individual variability in genes, environment, and lifestyle. This necessitates thorough preoperative risk stratification by anesthesiologists and the implementation of targeted, mechanism-based perioperative analgesia to intercept the neurobiological programming that underlies chronic pain and opioid dependence. Clinical translation includes increased rigor in pre-habilitation screening for psychosocial risk factors, outlines in Table 1 and mechanism-based anesthesia guided by targeted epigenetic knowledge outlines in Table 3. Future research must focus on validating integrated multimodal biosignatures to accurately identify high-risk individuals before surgery and on confirming the long-term clinical effectiveness of mechanism-targeted interventions, such as TIVA and adjunct non-opioids, in large-scale clinical trials.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Plinio Cirillo, University of Naples Federico II, Italy

Reviewed by: Ashish Malik, Indraprastha Apollo Hospitals, India