Preventing chronic pain after thoracic surgery: a narrative review of analgesic strategies

Introduction

Chronic post-surgical pain, defined as pain persisting beyond three months after a procedure, is a significant complication of thoracic surgery that affects approximately 47% of individuals (1-3). The pain is typically localized to the chest wall and frequently includes a neuropathic component due to intercostal nerve injury (up to 47%), which is associated with heightened pain intensity and sensory abnormalities such as hyperalgesia and allodynia (1,4).

Chronic pain after thoracic surgery (CPTS) is a multifactorial condition believed to arise from the interplay of various biological and psychosocial determinants (5,6). One of the risk factors that was identified is the surgical approach. Compared with thoracotomy, minimally invasive surgery (MIS)—including both video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS)—involves smaller incisions and results in less operative trauma, theoretically lowering the risk of persistent postoperative pain. However, comparative studies have demonstrated only a modest reduction in the incidence of CPTS with MIS, with reported rates ranging from 26% to 63% at 3 months postoperatively, and no difference in pain severity (5-10). While RATS is associated with a better recovery profile in the immediate postoperative period compared to VATS, there is no difference in the incidence of CPTS between the two approaches (10,11). This may be attributed to the continued mechanical trauma associated with multi-port VATS, and improved pain outcomes have been observed in cases with fewer ports, shorter operative times, and reduced duration of chest drainage (7,8).

Most patient-related risk factors that are associated with CPTS are non-modifiable and include female sex, young age, and postoperative chemo and radiation therapy (7,8). Predisposing psychological factors such as pain catastrophizing, anxiety, and depression were also associated with CPTS (3,6,9,12). However, the most consistent—and modifiable—predictor of CPTS is the presence of moderate to severe pain (numerical Rating Scale ≥4) within the first 3–7 days following surgery (3,5,7-9,13,14). Intense and sustained nociception induces changes in the dorsal horn of the spinal cord that promote central sensitization and microglial activation, potentially resulting in chronic pain (15). As higher acute pain scores are usually the result of inadequate analgesia, optimal management of acute postoperative pain may mitigate the transition to chronic pain (8,16). Although guidelines have been developed for the optimal management of acute postoperative pain, there remains no consensus on the most effective interventions to reduce the incidence of CPTS (17). A comprehensive review of the impact of various analgesic strategies on the development of chronic pain could aid thoracic surgeons and anesthesiologists in designing more effective postoperative pain management protocols and potentially improve long-term patient outcomes.

This article will provide a narrative review of the studies that evaluated the impact of various analgesic interventions on the incidence of CPTS. Some suggestions for a preventive postoperative pain management plan will be offered. This article is presented in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-26/rc).

Methods

A comprehensive search was performed using PubMed for articles published between January 1980 and April 2025. The search strategy involved various combinations of terms relevant to the topic: “chronic pain”, “thoracotomy surgery”, “video-assisted thoracoscopic surgery”, “robotic-assisted thoracoscopic surgery”, “post-thoracotomy pain”, “prevention”, “regional analgesia”, “thoracic epidural analgesia”, “nerve block”, “ketamine”, “dexmedetomidine”, “pregabalin”, “dexamethasone”, “cryoanalgesia”, “acetaminophen”, and “non-steroidal anti-inflammatory drugs” (Table 1). The search was limited to English-language, full-text publications involving adult populations. Studies examining chronic pain following chest wall surgery or cardiac surgery were excluded. Only randomized controlled trials (RCTs) and meta-analyses of RCTS comparing the effects of regional blocks or multimodal analgesic drugs with other interventions on the incidence of CPTS were included.

Results

Part I: regional analgesia

Nociceptive somatic afferents from the intercostal nerves (T3–8) represent the primary source of pain following thoracic surgery. However, visceral afferents transmitted via the vagal and phrenic nerves also contribute to pain (18) (Figure 1). Regional analgesia, through blockade of pain transmission from the injured site to the central nervous system, is one of the most effective means of reducing acute pain after thoracic surgery (16,17). This blockade also interrupts the initiation of central sensitization, a critical process in the development of chronic post-surgical pain (15). Regional techniques may involve single injections or continuous infusions via catheters, extending analgesia through the initial 48–72 postoperative hours. Several regional techniques targeting different anatomical sites have been evaluated for their potential to reduce CPTS: intercostal nerve block (ICNB), paravertebral block (PVB), thoracic epidural analgesia (TEA), and fascial plane blocks, including erector spinae plane block (ESPB) and serratus anterior plane block (SAPB). The evidence concerning thoracotomy and MIS is presented separately.

Figure 1 Sensory innervation of the thorax. Reused with permission from AME Publishing Company (Curr Chall Thorac Surg 2023;5:36).

Thoracotomy

Thoracotomy is among the most painful surgical procedures and necessitates an intensive analgesic approach, typically incorporating continuous regional analgesia unless contraindicated (19). Both TEA and PVB are effective for acute pain control, but their comparative effectiveness in preventing chronic pain remains unclear (19). When TEA is employed, combining local anesthetics with opioids is advised due to their synergistic effect, enhancing analgesia while minimizing hypotension (20). Although pre-emptive TEA may improve acute postoperative pain, it does not significantly reduce CPTS compared to postoperative initiation (21). For PVB, a continuous infusion for a minimum of 48 hours is strongly recommended; single-shot PVB has been associated with poorer analgesia and higher CPTS incidence at 3 and 6 months postoperatively compared with TEA (22). The benefit of intraoperative intercostal nerve cryoanalgesia has also been studied in patients undergoing thoracotomy. The theoretical basis for its use is long-lasting analgesia through neurolysis of the intercostal nerves. Few studies have evaluated its impact on CPTS; however, all reported an increased incidence of neuropathic pain characteristics up to 6 months after surgery in patients who received cryoanalgesia, compared to those who received epidural analgesia (23,24).

MIS

Regional analgesia is strongly recommended for acute pain management after MIS, though optimal techniques remain debated (17). Both PVB and ESPB, delivered as either single injections or continuous infusions, provide effective pain relief and are recommended (17,25,26). Only a limited number of RCTs have evaluated the impact of regional analgesia on the incidence of CPTS, and these have focused exclusively on VATS. A network meta-analysis indicated that TEA, PVB, and ICNB reduced chronic pain incidence compared to no regional analgesia, whereas SAPB was ineffective (16). One RCT found no significant difference in CPTS incidence between continuous ESPB and PVB [ESPB: 34% (12/35) vs PVB: 31% (11/35), P>0.8] while another showed that combining ESPB and PVB was more effective at reducing CPTS than ESPB alone (25,26). PVB with liposomal bupivacaine did not reduce the incidence of CPTS 3 months after VATS, compared with PVB with plain bupivacaine (27). Consequently, PVB and ESPB are recommended components of multimodal analgesia after VATS. However, there is insufficient evidence to favor continuous over single-shot techniques. SAPB is not recommended due to its inferior efficacy in reducing acute and chronic pain (17). While TEA and ICNB can reduce CPTS, TEA’s side effect profile and ICNB’s limited duration and risk of local anesthetic toxicity make them less favorable (17,19). Only one study evaluated the impact of intraoperative cryoablation of the intercostal nerves on the incidence of CPTS after VATS. There was no difference in the incidence or severity of chronic pain 3 and 6 months after the surgery (28).

PART II: pharmacologic interventions

Most pharmacologic agents investigated for CPTS prevention are also used for acute postoperative pain control (29). Though many have been evaluated across diverse surgical contexts, only a subset—namely ketamine, gabapentinoids, and α2-agonists—have been specifically studied for their role in preventing CPTS. Evidence was not found in the context of RATS or for other agents such as lidocaine and corticosteroids.

Ketamine

Ketamine is a hypnotic and analgesic drug that has been studied extensively for its role in the perioperative period. The mechanism supporting its role in preventing chronic pain after surgery is through the blockade of N-methyl-D-aspartate (NMDA) receptors, which are crucially implicated in the process of central sensitization and pain chronicization (15). Ketamine has also been shown to decrease wound and opioid-induced hyperalgesia, which are both associated with the development of CPTS (30,31). Studies on ketamine for CPTS prevention show mixed results, likely due to heterogeneity in dosing, timing, and duration.

In thoracotomy patients, one study found a single intraoperative dose (0.2 mg/kg) significantly reduced CPTS incidence and neuropathic features at 3 months (ketamine: 20.2%, placebo: 61.4%, P<0.001) (32). None of the patients had regional anesthesia in this study. However, two studies administering ketamine (0.1 mg/kg/h) intra- and postoperatively in combination with TEA reported no significant difference in CPTS incidence [ketamine 29% vs. placebo 26.7% (P=0.84); and ketamine 30% vs. placebo 24% (NS)] although pain scores in the first 3 days were lower in the ketamine group (33,34). These findings suggest that the analgesic efficacy of regional anesthesia may surpass that of ketamine, potentially masking its benefits. In the absence of regional analgesia, ketamine may help reduce CPTS by improving pain control and reducing opioid requirements (35). In VATS patients, epidural esketamine was associated with a significantly lower CPTS incidence than epidural morphine (3 months: esketamine: 17.5% vs. morphine: 34.2%, P=0.004) (36), though the concurrent use of opioid-free anesthesia in the esketamine group confounds interpretation (36). Two other studies comparing an intraoperative bolus of ketamine with and without a postoperative infusion found a decrease in the incidence of moderate to severe chronic pain 3 months after the surgery, although this was not statistically significant (placebo: 34%, ketamine 23%, P=0.11) (37,38). Thus, ketamine may reduce the incidence of CPTS after VATS, but further adequately powered studies are needed. Extending the infusion for 48 hours into the postoperative period might improve its efficacy (36,38).

Gabapentinoids

Pregabalin and gabapentin are agonists of the α2δ subunit of the presynaptic calcium channel, which results in decreased transmission of the nociceptive signal following nerve injury (39). Pregabalin has a more favorable pharmacokinetic profile, which partly explains its preference over gabapentin. Their efficacy in treating established neuropathic pain is well known, and since a neuropathic component is often implicated in CPTS, it has been hypothesized that gabapentinoids could reduce its incidence (1,4).

In a meta-analysis of four trials, perioperative pregabalin was associated with a modest reduction in pain scores 3 months after thoracotomy, although the incidence of CPTS was not specifically evaluated (40). Patients who received pregabalin exhibited significantly fewer neuropathic pain characteristics compared to control. However, side effects such as somnolence and dizziness were significantly more frequent in the pregabalin group. On the other hand, a sub-group analysis from a more recent meta-analysis failed to identify a reduction in the incidence of chronic pain with gabapentinoids following thoracotomy (29). Interestingly, pregabalin significantly improved pain control and reduced the incidence of chronic neuropathic pain after thoracotomy when administered to patients experiencing moderate to severe pain three days after the surgery, compared to placebo (41). These findings suggest that pregabalin may be more effective when targeted to patients whose pain persists in the first postoperative week, rather than when administered routinely in the perioperative period. In the context of VATS, pregabalin did not reduce pain severity at 3 months postoperatively, and the incidence of CPTS was not assessed (42,43). Nevertheless, patients in the pregabalin group also displayed fewer neuropathic pain characteristics (43).

Given the lack of strong evidence supporting gabapentinoids in reducing the incidence of CPTS and their associated adverse effects, routine use of gabapentinoids is not recommended after thoracic surgery (17,29,40,42-44). However, they may be considered in patients reporting moderate to severe postoperative pain despite multimodal analgesia, especially when neuropathic features are present (41).

Alpha-2 agonists

Dexmedetomidine, a highly selective α2-agonist with sedative, analgesic, and opioid-sparing properties, is particularly advantageous in the perioperative setting due to its lack of respiratory depressant effect (45). It is commonly administered as a perioperative infusion or as an adjunct to local anesthetics in peripheral nerve blocks, though some studies have reported its use in TEA (46). Most studies evaluating dexmedetomidine in thoracic surgery have observed analgesic and opioid-sparing effects in the postoperative period, although many did not incorporate basic analgesia [acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs)], limiting its generalizability (17,47). Its role in preventing CPTS remains poorly characterized. In thoracotomy surgery, only two studies have examined the impact of intravenous (i.v.) dexmedetomidine on the occurrence of CPTS and they yielded conflicting outcomes (48,49). Conversely, one study comparing i.v. dexmedetomidine to placebo during VATS showed a reduced incidence of chronic pain 3 months after surgery (47).

The protective effect of dexmedetomidine has been assessed more thoroughly when used perineurally as an adjunct to local anesthetics. Indeed, adjuncts such as dexmedetomidine and dexamethasone can extend the analgesic duration of a single-shot nerve block by 6–8 hours (50). In one study, continuous PVB with dexmedetomidine and ropivacaine reduced the incidence of CPTS after thoracotomy (dexmedetomidine: 69.2%, placebo: 50%, P=0.49), although the reduction was not statistically significant due to the limited power of the study (51). Another study showed that dexmedetomidine added to local anesthetics in the ESPB was as effective as TEA in reducing the incidence of CPTS after thoracotomy, and more effective than ESPB alone (TEA: 11.5%, ESPB with dexmedetomidine: 16%, ESPB alone: 48.2%, P=0.004) (52). A similar effect was noted after VATS: one study using 1 µg/kg dexmedetomidine and local anesthetics in single-shot PVB reported a lower incidence of CPTS at 3 months (dexmedetomidine: 3%, ropivacaine alone: 25%, P=0.005), and another one found fewer neuropathic pain features 3 months after surgery, though the incidence of CPTS was not directly assessed (53,54). In summary, perineural dexmedetomidine may reduce the incidence of CPTS when used as an adjunct to local anesthetics, likely by prolonging nerve block duration and enhancing postoperative analgesia while decreasing opioid use (45,51-54). More studies are required to determine its role when administered intravenously. Bradycardia and hypotension are common adverse effects after dexmedetomidine and it should not be used in patients with cardiac disease or conduction abnormalities (17).

PART III: optimizing the management of acute pain

As discussed, moderate to severe postoperative pain in the initial days following surgery is the strongest predictor for the development of CPTS, underscoring the importance of effective pain management. Intense and sustained nociceptive input form the surgical site induces changes in the dorsal horn of the spinal cord that promote central sensitization and microglial activation, potentially resulting in chronic pain (15). Nociception signaling begins with surgical incision, peaks during the first three days after surgery, and then gradually decreases over the course of the following weeks (5). Consequently, analgesic interventions must begin intraoperatively and continue for several days postoperatively to effectively prevent central sensitization (15). Historically, opioids have been the cornerstone of perioperative pain management, but evidence indicates that higher opioid doses lead to enhanced central sensitization and increased risk of chronic pain (15,30). Therefore, multimodal analgesia aimed at optimizing pain control while minimizing opioid use is essential to reduce the incidence of CPTS.

The use of regional anesthesia is strongly recommended, as it provides superior analgesia and reduces opioid requirements (17) (Figure 2). For thoracotomy, TEA or continuous PVB are the most effective options and should ideally be initiated prior to surgical incision to decrease intraoperative opioid needs and improve postoperative analgesia (21,22). In MIS, both single-shot and continuous catheter-based blocks provide effective postoperative analgesia with no clear advantage of one over the other. Performing single injection blocks before the surgery allows for a reduction in intraoperative opioid requirements but, unlike continuous blocks, they have a limited analgesic duration which limits their benefit in the postoperative period (55). The addition of dexmedetomidine to the local anesthetic mixture can mitigate this problem, but another option is to use i.v. ketamine and/or dexmedetomidine intraoperatively followed by the single-shot regional block at the end of surgery (50). Indeed, i.v. dexmedetomidine and ketamine can both significantly reduce the use of opioids during the intraoperative and early postoperative period, and performing the block at the end of surgery maximizes its analgesic benefits during the postoperative period (38,56,57). Total intravenous anesthesia (TIVA) may be preferable to sevoflurane for anesthesia maintenance because one study reported a decreased incidence of CPTS 3 and 6 months after thoracotomy in the TIVA group (58).

Figure 2 Suggested postoperative pain management plan aiming to reduce the incidence of chronic pain after thoracotomy and VATS. COX-2, cyclooxygenase-2; NSAID, non-steroidal anti-inflammatory drug; PCA, patient-controlled analgesia; PVB, paravertebral block; TEA, thoracic epidural analgesia; VATS, video-assisted thoracoscopic surgery.

Despite regional anesthesia techniques, most patients experience postoperative pain when the block wears off or in cases of incomplete coverage of the surgical site by the block or failed block. Acetaminophen and NSAIDs [or cyclooxygenase-2 (COX-2) specific inhibitor] have analgesic and opioid-sparing properties and they should be co-administered pre-operatively and continued around-the-clock postoperatively for at least 7 days unless contraindicated (15). Residual pain should be treated with complementary on-demand opioids (17). The addition of ketamine to the patient-controlled opioid analgesia should be considered as it decreases the proportion of patients with moderate to severe pain and reduces postoperative opioid requirements (36,57,59). The postoperative use of pregabalin and dexmedetomidine is generally not advised because of their side effect profile and uncertain benefit in the presence of basic and regional analgesia (17,44). However, pregabalin may significantly improve analgesia when administered to patients who suffer from moderate to severe pain despite multimodal analgesia, especially when neuropathic features are present (41).

Limitations

Narrative reviews lack methodological standardization and are susceptible to subjective bias. In this review, efforts were made to comprehensively search the literature and to emphasize studies of higher methodological quality when synthesizing findings. Nonetheless, subjectivity cannot be eliminated completely. Additionally, expanding the range of databases searched might have identified further studies, although over forty RCT and meta-analyses were analyzed in this review. The conclusions of this review are limited by the low methodological quality of many included studies. Indeed, most studies carried a significant risk of bias and were underpowered to adequately evaluate the impact of the intervention on chronic pain. The definition of chronic pain also varied greatly between the studies, making it difficult to draw definitive conclusions. For example, a significant number of studies used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score as a marker of CPTS, instead of the more widely accepted Verbal Rating Scale score. The LANSS score was designed to identify pain of neuropathic origin, and because only half of patients with CPTS have neuropathic pain, a negative score could result in underdiagnosis. Finally, many studies did not use co-analgesia with acetaminophen and/or NSAIDs in their study protocol, making the added benefit of these interventions uncertain within a multimodal protocol.

Conclusions

Despite advances in surgical techniques and perioperative care, chronic pain remains prevalent after thoracic surgery. The most important predictor of CPTS is moderate to severe pain during the first postoperative days, indicating that aggressive management of acute pain may be the most efficient preventive intervention. Regional analgesia appears to be the most effective intervention for reducing the incidence of CPTS and should be routinely employed. Other interventions such as ketamine, dexmedetomidine, and pregabalin may be useful in select patient populations and can be considered. Further well-designed studies specifically evaluating chronic pain prevention within a multimodal framework are needed to draw more definitive conclusions.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-26/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-26/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-26/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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