FormalPara Key Summary Points

Chronic pain after lung transplantation (LTx) can substantially reduce quality of life, yet current consensus guidelines say little about how to prevent or manage it.

As reported, 18–70% of patients experience chronic pain after LTx, with 10-25% of all patients experiencing moderate or severe chronic pain.

The literature has identified several pre-, intra-, and postoperative risk factors for chronic pain after surgery, though few of those studies have focused on LTx.

Research is urgently needed on how to identify patients at higher risk of chronic pain after LTx and on the most effective methods for treating or even preventing it.

Introduction

Lung transplantation (LTx), when feasible, is an effective treatment for end-stage lung disease, reducing physical disability and mental impairment, prolonging survival, and improving health-related quality of life (QoL) [1]. Survival after LTx has become as high as 85% after 1 year and 59% after 5 years as a result of advances in donor selection, organ preservation, perioperative management, and treatment or prevention of postoperative complications [2, 3]. With improved survival rates and prolonged survival times, there has been an increase in the number of lung transplant recipients experiencing persistent postoperative complications, resulting in a decline in patient satisfaction and QoL [4]. Consequently, alongside an emphasis on survival, there has been a growing interest in improving post-transplant recovery and enhancing health-related QoL for these individuals. Many patients, however, suffer chronic pain after LTx, which severely reduces QoL [5]. In fact, the incidence of pain after LTx may be higher than that after other types of thoracotomy [6].

This higher incidence likely has several explanations. One is that before LTx, most patients are relatively frail and anxious [7] and most suffer pain that often must be treated with opioids [4]. Research suggests that preoperative pain is an independent risk factor for postoperative pain [8]. Another is that LTx is extremely traumatic: the use of a chest expander and the disarticulation of muscle and costal cartilage injure muscle, pleural, and intercostal nerves. A third contributor is that postoperative care often involves invasive procedures such as placement of indwelling tubes and fiberoptic bronchoscopy. Lastly, the evaluation of postoperative pain presents a significant challenge owing to the multiple postoperative complications that typically occur [9].

Pain after LTx may be acute, resolving quickly during incision healing after surgery; but in a significant proportion of patients, the pain may become chronic, persisting for years or even a lifetime [10]. Such chronic pain can strongly reduce QoL and increase health care costs [11], in part by increasing risk of chronic opioid use and psychiatric disorders [12]. Therefore, chronic pain should be recognized as a considerable problem affecting post-LTx health.

Nevertheless, most research on pain after LTx has focused on acute pain, and the emergence of chronic postsurgical pain (CPSP) after discharge is poorly understood by patients and healthcare professionals. It was not until 2019 that the revised 11th edition of the International Classification of Diseases (ICD-11) [13] included CPSP as one of the systematic classifications of chronic pain and established diagnostic criteria for CPSP. Prior to this, the lack of an appropriate diagnostic classification system hindered the identification and diagnosis of patients with this type of pain, which has exacted a heavy toll on both research and treatment of CPSP [14].

Regrettably, research on CPSP and consensus guidelines on its treatment or prevention—especially in the case of LTx—are sorely lacking, and little information is available in standardized pain management regimens. The challenges in the management of CPSP in LTx patients are heterogeneity of primary disease before transplantation, patient demographics and surgical access, as well as the use of extracorporeal life support. These challenges complicate the formulation of standardized regimens for managing postoperative pain. Therefore, preventing the occurrence of CPSP and halting its development in LTx patients is an important goal [15].

The present narrative review aims to consolidate existing knowledge about the epidemiology, clinical characteristics, and risk factors of chronic pain after LTx as well as effective methods to treat or prevent it. In this way, the review aims to serve as a valuable resource for health care professionals. In parallel, the review identifies questions and issues that demand future study in order to develop consensus guidelines for treatment and prevention.

Selection of Evidence

Papers for this narrative review were collected in several databases including PubMed, Medline, Embase, Cochrane databases, and Web of Science. The final search strategy was as follows: (“Pain, Postoperative”[Mesh] OR (“persistent pain” AND surgery) OR (“chronic postsurgical pain”) OR (“chronic post surgical pain”) OR cpsp OR (“persistent postoperative pain”) OR (“chronic postoperative pain”) OR (“chronic pain” AND surgery)) AND (“lung transplantation” [Mesh] OR “lung transplant*”). Publication date constraints were not considered and no grey literature was included. The search was last updated in January 2024. The authors determined inclusion on the basis of the papers’ relevance to the topic; 26 papers were finally included. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Diagnosis of Chronic Pain After LTx

Definite diagnostic criteria are required to distinguish CPSP from other disorders. Over the past 20 years, the definition of CPSP has evolved as research advanced, and the definition has been continuously revised in terms of pain duration, pain source, spatial distribution, and characteristics [16,17,18]. Until the International Association for the Study of Pain (IASP) included CPSP in the new ICD-11, CPSP was listed as one of seven categories of chronic pain [13]. CPSP is currently defined as pain that meets the following criteria [13]:

  • Pain develops after surgery or increases intensity of pain after surgery

  • Pain should persist for at least 3 months with a noticeably negative impact on QoL

  • Pain may appear after a pain-free period after surgery, or it may be a continuation of acute postsurgical pain

  • Pain is either localized to the surgical field or to a referred area (e.g., innervation territory, referred dermatome for visceral surgery)

  • Other possible causes for the pain have been excluded (e.g., infection, cancer recurrence)

The detailed pathways underlying CPSP remain poorly understood. The pain is usually described as mild or moderate tingling or burning. Several studies have suggested that the pain is primarily neuropathic in origin [13, 19, 20], but at least one study has suggested that this may not be the case for chronic pain after LTx [8]. The diagnosis of CPSP mainly relies on three aspects: the quality, location, and duration of pain. Diagnosing CPSP can be as complex as diagnosing neuropathic pain, and it requires comprehensive information about the case. However, it is difficult to obtain comprehensive information in clinical studies, especially preoperative information and physical tests, depending on the type of study. As a result, the incidences of CPSP reported in clinical studies may be less accurate.

Incidence of Chronic Pain After LTx

The incidence of chronic pain after different types of surgical procedures varies from 3 to 85%, and QoL is severely affected in 2–25% of patients with CPSP [21, 22]. For example, the incidence of chronic pain after mastectomy ranges from 20 to 50%, while that after thoracotomy ranges from 5 to 65% [10], which makes comparisons of the incidence across studies challenging. Several studies on chronic pain after LTx have been performed, showing that 18–70% of patients experience chronic pain after LTx, with 10–25% of all patients experiencing moderate or severe chronic pain [8, 22,23,24,25,26,27,28]. The incidence of CPSP in patients after LTx is higher than that in patients after most other procedures, including general thoracotomy, though direct comparisons are hampered by the wide variation in incidence. The wide range of the incidence of chronic pain following LTx may be attributed to various factors, including the different types of incisions, whether sternotomy, thoracotomy, or clamshell incision; pain assessment tools, whether unidimensional (numeric rating scale, visual analogue scale) or multidimensional (e.g., McGill Pain Questionnaire, Brief Pain Inventory, 13-item Pain Catastrophizing Scale); and the timing of pain assessment, typically from 2 months to 5 years.

Several studies have provided insights into the incidence of chronic pain after LTx (Table 1). Sampling of 117 patients at multiple sites in Sweden [25] reported incidence of 65.5%, and one-quarter of patients reported moderately severe pain, defined as a score > 9 on the visual analogue scale of Pain-O-Meter. This incidence should be interpreted with caution given that the study did not describe how potential causes of the pain other than transplantation were excluded, such as infection, calmodulin phosphatase inhibitor-induced pain syndrome, and side effects of immunosuppressive medications other than calcineurin inhibitors. The incidence of 49% reported in a study of patients in Canada [23] may also be an overestimate because pain was assessed using the Brief Pain Inventory, which does not specifically identify chronic pain. This means that patients who show the presence of pain on the BPI do not necessarily have chronic pain. A lower, potentially more reliable estimate of incidence may be 18% in a study of 79 patients in Denmark [24], and the pain in 85% of affected patients was moderate or severe, defined as ≥ 3 of 10 on a numerical rating scale. That study assessed pain using dichotomous and graded scales, it differentiated pain with different origins, and it measured the impact of pain on daily activity. In contrast, a much smaller study of 20 patients in Denmark [22] reported an incidence of 70%. The pain in most affected patients showed sensory characteristics of neuropathic pain. An intermediate incidence of 57.8% was reported in a study of 64 patients in the USA [27], and only 16.3% of the affected patients reported moderate or severe pain (defined as ≥ 5 of 10 on a numerical rating scale), which may be attributed to the fact that 90% of the patients received epidural analgesia following transplantation. In fact, epidural analgesia may reduce the incidence and intensity of chronic pain after open heart surgery [29].

Table 1 Characteristics of key studies of chronic pain after lung transplantation
Full size table

One factor that may limit the reliability of the estimates of incidence is the timing of pain assessment after LTx, which is an inherent limitation of cross-sectional studies. For example, pain prevalence in the above-mentioned study in Sweden [25] increased from 51% at 1 year after transplantation to 75% at 4 years, declining to 54.5% at 5 years. Another study showed that pain scores decreased continuously during follow-up after discharge [26]. A third study found that prevalence of chronic pain decreased from 47.2% at 3–11 months after transplantation to 40.7% at 39–55 months [28]. Unfortunately, these studies did not analyze pain recovery trajectories in detail, which may help clarify the transition from acute to chronic pain after LTx. Studies with long-term follow-up are needed to explore this question and to identify factors that can prolong pain and delay recovery. Future studies should analyze relatively large samples, which in light of the relatively small number of LTx conducted at single medical centers, argues for multi-center research collaborations.

Most studies of incidence did not differentiate between whether chronic pain after LTx was new-onset pain or a continuation of preoperative pain. One study that did differentiate between the two types of chronic pain found that 42 (58.3%) patients had preoperative pain and 49 (68.0%) suffered from postoperative pain [8]. These findings may not be generalizable to all lung transplant recipients because most patients in that study had cystic fibrosis without primary pulmonary hypertension and most received epidural analgesia. Future research should comprehensively collect perioperative data to differentiate “new-onset” and “continuation” chronic pain after LTx, examine whether it can be mitigated or prevented through epidural analgesia [30], and identify pre- and intraoperative risk factors.

Risk Factors of Chronic Pain After LTx

The literature has identified several pre-, intra-, and postoperative risk factors for chronic pain after surgery, though few of those studies have focused on LTx.

Pre-operative Risk Factors

Sex, age, and certain genetic signatures have been linked to risk of CPSP [11, 21, 31, 32], but results from studies focusing on lung transplant recipients are scarce and conflicting. For example, one study linked patient-related factors to greater risk of chronic pain and sensory abnormalities in patients undergoing bilateral LTx [33], but another study did not detect significant associations of sex, age, preoperative activity level, or preoperative QoL with risk of chronic pain after bilateral LTx [8]. Moreover, the link between genetic factors and chronic pain is complex and there is strong evidence that polymorphisms in some genes are closely associated with CPSP [31, 32], but whether they are specifically associated with chronic pain after LTx is unclear. Future evidence from more patient populations is necessary to analyze the impact of patient-related factors, and more in-depth studies are needed to explore the mechanism of gene action in chronic pain.

Preoperative hypertension, anxiety, depression, and other psychosocial factors, which can influence pain perception [34], may affect risk of CPSP. Indeed, one meta-analysis concluded that preoperative psychosocial factors could influence the transition from acute to CPSP [35]. Whether the same is true for lung transplant recipients is unclear. One study linked pre-transplant depression or anxiety to higher risk of chronic pain [26]. If future work can confirm such associations, clinicians may need to consider pre-transplant psychological interventions for certain patients, which could take the form of psychopharmacological, cognitive behavioral, or relaxation-based therapies.

A preoperative factor that the literature clearly links to risk of chronic pain after LTx is preoperative chronic pain. An analysis of more than 11,500 lung transplant recipients demonstrated a strong association between pre- and post-transplant opioid use [36]. A much smaller study showed that maximum pain score before transplantation independently predicted pain at 6 months after surgery [8]. Indeed, preoperative chronic pain, whether in the surgical area or elsewhere, is a risk factor for CPSP in many clinical contexts [22]. A likely explanation is that prolonged pain sensitizes the peripheral and central nervous systems, potentially through various excitatory pathways [37, 38].

More studies are needed to identify preoperative factors, including genetic signatures, that influence risk and severity of chronic pain after LTx.

Intra-operative Risk Factors

The various types of incision used for LTx, including anterolateral or posterolateral thoracotomy, median sternotomy and clamshell incision [39], vary in size, location, and degree of injury to muscles and nerves. Therefore it stands to reason that the type of incision used during LTx should influence risk of chronic pain afterwards. There is indeed some evidence to support this, although it is limited [40]. For example, one study linked the clamshell incision to significantly higher risk of chronic pain than median sternotomy [41]. Thoracotomy for LTx has been associated with greater acute pain but less postoperative bleeding as well as shorter mechanical ventilation and residence in the intensive care unit(ICU) than the other two types of incision [42]. In clinical contexts for other thoracic surgery, posterolateral thoracotomy has been linked to more severe CPSP than an anterolateral approach [43, 44]. The evidence seems sufficient to conclude that clinicians should consider risk of postoperative pain when deciding on the most appropriate surgical approach for LTx.

Intra-operative nerve injury may be a risk factor for CPSP [45, 46], but whether it affects risk of pain after LTx is unclear. Future studies should examine whether rib removal, type of intercostal nerve handling, and extent of nerve injury can influence such risk. Clarifying whether and how nerve injury contributes to chronic pain after LTx will require more detailed analysis of the symptoms of chronic pain after transplant surgery, particularly neuropathic symptoms.

Future studies should also consider potential contributions from inflammation of the pleura and lung parenchyma, extent of trauma, immunosuppression and duration of transplantation surgery [10]. Another likely contributor is the type of anesthesia, which has been shown to affect risk and severity of CPSP in various clinical contexts [47, 48], yet it has not been systematically analyzed in the case of LTx.

Postoperative Risk Factors

Several clinical trials have demonstrated a correlation between the severity of acute pain and chronic pain after thoracotomy [49,50,51]. In the last two decades, the mechanisms of the transition from acute pain to chronic pain have attracted increasing attention, and this association suggests that effective acute pain management may reduce the incidence of CPSP [10, 21]. Finnerup et al. [52] suggested the presence of several unfavorable postoperative pain trajectories, including those of persistent or exacerbating pain, and they elaborated on the transition from acute to chronic pain. The transition of the underlying pain mechanisms underlines the importance of aggressively treating acute pain in order to prevent CPSP [53]. Despite the validation of this approach in other thoracotomy procedures, fewer studies have been conducted related to chronic pain after LTx and, to date, there is no evidence of a causal relationship between acute pain and chronic pain after LTx.

Different methods of postoperative analgesia and poor control of acute pain may have a significant impact on pain outcomes [54, 55]. In a retrospective study, 50 of 150 discharged patients (33%) were taking opioids at 2 months after LTx, and oral opioid use was associated with significantly higher CPSP [26]. Nevertheless, the relationship between opioid use and CPSP remains to be confirmed in randomized controlled trials. With the development of ultrasound technology, various regional block methods have become popular for providing perioperative analgesia in LTx, but there is insufficient information on how intra-, peri- and postoperative factors, such as the consumption of analgesics, affect risk, and characteristics of CPSP.

Postoperative psychiatric comorbidity may influence risk of chronic pain after LTx: in one analysis of the risk factors for CPSP, score on the Center for Epidemiologic Studies Depression Scale was the strongest predictor of pain score on a numerical rating scale at 2 months postoperatively [26]. Several studies have investigated the postoperative short- and long-term mental health of lung transplant recipients [56,57,58]. One such study revealed that nearly 20% had depression in the first year post-transplant, while 44% of individuals with pre-transplant anxiety developed diagnosable anxiety during the same timeframe, impacting their recovery process [58]. Of concern, the prevalence of post-traumatic stress disorder among lung transplant recipients, at 12.6%, is twice that of the general population [56]. Symptoms of post-traumatic stress disorder were shown to have a detrimental effect on the recipients’ health-related QoL, including pain scores [59]. A meta-analysis concluded that psychosocial factors could influence the transition from acute to chronic postoperative pain in various clinical contexts [35]. In fact, psychosocial interventions such as self-hypnosis and psychoeducation soon after various types of surgery can prevent or mitigate CPSP and opioid use [60, 61]. Future work should explore whether the same is true of patients undergoing LTx.

Strategies to Treat or Prevent Chronic Pain After LTx

Minimizing or even preventing chronic pain requires combinations of interventions that aim to minimize tissue trauma, acute pain and other risk factors. Identifying the full range of risk factors is therefore critical for designing comprehensive treatments and preventive methods.

As mentioned, postoperative pain is linked to surgical trauma, specifically related to soft tissue damage, muscle manipulation, rib fractures, and intercostal nerve injuries. The severity of the surgical insult and subsequent inflammatory reaction can contribute to the development of chronic pain after LTx [42]. Surgeons should employ a safe approach that ensures sufficient exposure and minimizes surgical trauma. A recent study by Thomas et al. investigated the advantages of utilizing a 6–8 cm skin incision for LTx, utilizing minimally invasive instruments and knot pushing devices [62]. They found that the minimally invasive LTx technique demonstrate potential benefits over conventional methods, such as decreased length of stay in the ICU and hospital, reduced opioid consumption upon discharge, and enhanced early lung function [62]. Notably, the selection of analgesic method and dosage of analgesic medication may be impacted by the precise location and size of the surgical incision. Furthermore, future assessments of the effectiveness of pain management strategies should be tailored to the specific surgical incision.

Local analgesia can be quite effective after general thoracic surgery and regional anesthesia can significantly reduce the incidence of CPSP [63], but whether the same is true for patients undergoing LTx remains to be seen. Future research should examine this question, especially since a wide range of analgesia methods have been applied successfully to such patients [64]. One study [64] summarized the advantages and disadvantages of different regional analgesic modalities for LTx. Anticoagulation treatment of extracorporeal life support limits the application of thoracic segmental epidural analgesia for LTx procedures. The thoracic paravertebral block, serratus anterior plane block, erector spinae plane block, thoracic nerve block, intercostal nerve block, and cryoablation techniques have also been used for local analgesia during and after LTx [64], and these new techniques may be promising analgesic approaches for LTx surgery. Recently, research from our medical center has shown that postoperative multimodal analgesia involving the combination of a serratus anterior plane block catheter and systemic analgesia can control post-transplantation pain effectively. Several studies have demonstrated the efficacy of intrathecal morphine for postoperative analgesia in cardiothoracic surgery [65, 66]; however, there is a paucity of evidence regarding its applicability in LTx. Additionally, the potential for respiratory depression necessitates careful consideration of its safety issues. Indeed, multimodal analgesia can reduce the neuropathic component of postoperative pain after thoracotomy in various clinical contexts, which in turn may decrease the incidence of CPSP [67, 68], a possibility that should be explored for lung transplant recipients. In this regard, a multimodal approach combining complementary systemic and local analgesia may be most effective for achieving synergies and minimizing adverse effects [64]. Overall, studies of local analgesic techniques in LTx are scarce and involve mostly case reports or case series, so the level of evidence is weak. Secondly, existing studies have focused on the efficacy of analgesic modalities during the perioperative period, while fewer studies have examined their efficacy against chronic pain after LTx [69,70,71,72].

The bio-psycho-social model has gained widespread acceptance as the most comprehensive approach for managing chronic pain [73]. Multimodal and multidisciplinary rehabilitation programs present the most promising avenue for enhancing pain relief and other patient-reported outcomes [74]. Therefore, incorporating psychological interventions into these multimodal analgesic programs is essential. Specifically, the potential for psychiatric disorders to influence postoperative pain implies that perioperative interventions, such as those based on cognitive-behavioral or relaxation therapies, may reduce the incidence of CPSP, as demonstrated in various clinical contexts [75]. Whether this is also true for lung transplant recipients is unclear, but at least one study supports the idea [76]. Further research on this question is warranted.

Thoracotomy for LTx requires separating the pectoralis, serratus anterior, intercostal, and transversus thoracis muscles. Postoperative rehabilitation exercises of the upper torso may reduce postoperative pain and strengthen muscles, at least in the short term [77]. In fact, postoperative rehabilitation is standard practice at most LTx centers around the world [78], yet evidence of its safety and efficacy is lacking. This should be urgently explored in future work.

In addition, lung transplant recipients are often characterized by a longer duration of mechanical ventilation and ICU stay [9]. Comprehensive ICU care and mental well-being of patients in the ICU have been associated with the prognosis of chronic pain [79]. Therefore, it is crucial to prioritize pain prevention strategies during the ICU phase of lung transplant patients, such as implementing multimodal pain management, integrated mind–body interventions, and fostering multidisciplinary collaboration.

Future work is also needed to explore the efficacy of other treatments against CPSP that have yet to be systematically explored in lung transplant recipients, which include non-steroidal anti-inflammatory drugs, tricyclic antidepressants, anti-epileptics, and low-dose opioids [40]. Optimization and development of next-generation treatments will likely be necessary because these drug regimens often prove ineffective among patients undergoing general thoracic surgery. Some patients may require multidisciplinary pain management involving different combinations of nerve block, physical therapy, sympathectomy, cryosurgery, epidural analgesia, and long-term neuromodulation through spinal cord stimulation. The complexity of treating chronic pain after LTx highlights the importance of stopping it before it starts, which requires elucidating its causes, underlying pathways, and typical trajectories.

Conclusions

Research is urgently needed on how to identify patients at higher risk of chronic pain after LTx and on the most effective methods for treating or even preventing it. While such research can draw partially on what is already known about CPSP after other invasive procedures, it must focus on lung transplant recipients because of the particularity of the procedure. Regional blocks, psychological interventions, postoperative rehabilitation training, and multimodal analgesia may reduce the incidence of CPSP and improve the trajectory of pain development. A wider adoption of best perioperative and intraoperative pain management practice is required. Our center is currently exploring the efficacy of multimodal analgesic strategies to control pain after LTx, such as combining an anterior serratus plane block catheter with systemic analgesia. We advocate for robust follow-up and management by a multidisciplinary team to facilitate timely identification of patients at risk for CPSP and prompt implementation of interventions. In this review, we identified many challenges in current research on chronic pain after LTx, including missing data, lack of clarity on the causes and nature of pain, differences in the diagnosis of CPSP, and absence of large-scale cohorts. The current literature comprises mainly a small number of heterogeneous studies reporting low-grade evidence, suggesting the need for high-quality prospective studies, preferably involving patients from multiple centers. Future studies on chronic pain after LTx should include sufficient preoperative data (e.g., pain assessment, psychophysiological status), detailed records of surgical approach (incision type, manipulation of nerve and muscle), postoperative interventions (pain management regimens, functional exercise, psychological interventions, etc.), assessment of acute postsurgical pain (intensity, characteristics and trajectory of pain development), and long-term follow-up (multidimensional pain assessment, identification of pain quality, QoL, etc.). Such work may aid in the early identification of lung transplant patients at higher risk of CPSP and in the design of timely interventions. In addition, an in-depth exploration of the mechanisms of chronic pain after LTx and the development of multicenter studies to improve pain management strategies in clinical practice would be promising.