Thoracic Anesthesia


Postoperative Management of Thoracic Surgical Patients


22. Routine Postoperative Care of the Thoracic Surgical Patient


Acute and Chronic Post-Thoracotomy Pain

Srinivas Pyati
David R. Lindsay
Thomas Buchheit

Key Points

1. Without adequate analgesia, most patients would experience severe pain following thoracic surgery.

2. Epidural analgesia is widely practiced and has been shown to provide superior pain relief compared with systemic opioids.

3. Multimodal analgesic strategies improve overall outcomes including patient satisfaction.

4. Chronic post-thoracotomy pain (CPTP) is common and remains a challenging condition to treat. Further investigation into prevention of this syndrome is needed.

Clinical Vignette

The patient is a 64-year-old man who underwent a left thoracotomy and extrapleural pneumonectomy for mesothelioma. A mid-thoracic epidural catheter was placed preoperatively and used to deliver 0.6mg of hydromorphone prior to incision. Intraoperatively, no medications were administered through the epidural catheter to avoid sympathectomy and hemodynamic instability.

Upon the patient’s arrival to the intensive care unit, an epidural infusion of bupivacaine 0.125% and hydromorphone 10 mcg/mL was initiated at 6 mL/h. The patient initially experienced 8/10 pain, requiring an epidural bolus of local anesthetic and an increase of the infusion rate. These adjustments resulted in reduction of his pain to 3/10. With improved analgesia, the patient was able to improve incentive spirometry performance, but he still continued to experience shoulder pain. He continued to do well with adequate pain control in the intensive care unit (pain score 3-5/10). His epidural was discontinued on postoperative day 3. He was discharged to home on postoperative day 5 with oral oxycodone as needed.

At his 2-month postoperative evaluation, the patient complained of significant chest wall pain localized to the thoracotomy incision. He described his pain as burning and aching.

The importance of postoperative pain management is well established.1 Postoperative pain following thoracic procedures causes a reversible restrictive pattern of ventilation with a decrease in vital capacity (VC) and functional residual capacity (FRC), impaired cough, rapid, shallow breathing, and often retention of secretions. These physiologic changes are particularly significant in thoracic surgery patients with preexisting pulmonary comorbidities, and may result in atelectasis, hypoxemia, and respiratory failure.2 Effective postoperative analgesia is of critical importance in these individuals. Nonetheless, effective treatment strategies for acute and chronic post-thoracotomy pain remain a significant challenge.3,4

The adverse effects of poor analgesia are not limited to the pulmonary system. Pain has been associated with increased myocardial oxygen demand, myocardial dysfunction, increased catecholamine release, poor glycemic control, deep vein thrombosis, and pulmonary embolism.5,6 These complications of inadequate pain control have been shown to lead to increased mortality and morbidity, prolonged length of hospitalization, and increased cost of patient care.7,8 In addition, several recent retrospective reviews suggest that a higher intensity of early (first week) postoperative pain is a risk factor for development of persistent pain.9,10

In this chapter, we will briefly review the mechanisms of thoracic pain. We will then discuss management strategies for acute postoperative pain and outline key concepts regarding chronic post-thoracotomy pain. The reader is referred to Chapter 6 for a more detailed discussion on the mechanisms of thoracic pain.


Nociceptive impulses from the thoracotomy incision, chest tube site, rib, muscle, and parietal pleural damage are transmitted along the intercostal nerves to the dorsal horn of the spinal cord. The autonomic nerves transmit noxious input from damaged visceral pleura. Pleural and bronchial manipulation may signal visceral pain through the afferent fibers of the vagus and phrenic nerves, which appear to be responsible for shoulder pain in some cases of acute and persistent pain.11,12

Tissue disruption triggers the release of inflammatory mediators such as prostaglandins, histamine, bradykinins, and potassium. These inflammatory mediators can directly activate nociceptors or enhance nociceptor activity. Furthermore, they cause a reduction in the pain threshold of the peripheral nerves. As a result, the severity of pain experienced by mechanical stimuli such as coughing or deep breathing may be intensified.13 This process is known as peripheral sensitization. Continued nociceptive stimulation will cause hyper-excitability of the nerves in the dorsal horn and other central pain centers, a process known as central sensitization.14 Central sensitization lowers the pain threshold of dorsal neurons and is associated with activation of NMDA receptors via substance P, calcitonin Gene Related Peptide (CGRP), and glutamate.15 Additionally, ongoing nociceptive stimulation alters neural function, resulting in neuroplasticity within the central nervous system. Despite the healing of tissue injury and the absence of inflammation, some patients continue to experience pain via central mechanisms (Figure 24-1).


Figure 24–1. Mechanisms of acute and chronic pain. (Modified from Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(13):185-211, with permission from Adis. © Springer International Publishing AG 2007. All rights reserved.)


It is estimated that more than 70% patients undergoing thoracotomy experience moderate to severe pain,16 even when a minimally invasive surgical approach is employed. Appropriate treatment of pain is necessary not only to prevent discomfort but also to prevent other negative sequelae. Despite effective management of somatic pain, some patients also complain of ipsilateral shoulder discomfort, occasionally severe in nature. The etiology of this visceral component of post-thoracotomy pain is suggested to be from contributions of the phrenic and vagus nerves.17 The phrenic nerve supplies sensory branches to the diaphragmatic and mediastinal pleura and the pericardium. Although clinicians may have reservations about phrenic nerve infiltration and diminished pulmonary function, this does not appear to manifest clinically.17,18 When evaluating patients before surgery, it is important to determine whether they have preexisting pain in the area of the proposed surgery, to document the intensity of such pain, and to note any preoperative narcotic use. The presence of preexisting pain may indicate greater difficulty in management of postoperative pain, necessitating a more aggressive analgesic approach. Pain assessment is often performed using the visual analogue scale (0-10) or another more sophisticated pain assessment tool, such as the brief pain inventory or McGill pain questionnaire.

Because of the involvement of multiple pain generators from the chest wall, viscera, and the parietal, diaphragmatic and mediastinal pleura, post-thoracotomy pain can be difficult to treat with a single analgesic modality. An ideal analgesic combination should reduce the intensity of movement-related pain, decrease the surgical stress response, and reduce the duration of hospitalization. Several techniques are employed to manage acute post-thoracotomy pain. For the purpose of this discussion, it is most convenient to treat each modality separately and to bear in mind that a multimodal analgesic approach is the most effective management strategy to control moderate to severe pain19 (Figure 24-2). Multimodal strategies may include epidural analgesia, local anesthetic infiltration, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant medications (Table 24-1). Preoperative insertion of a thoracic epidural catheter is commonly performed to provide analgesia during the perioperative period. If an epidural catheter cannot be inserted, paravertebral blocks are the preferred analgesic technique. In a survey of post-thoracotomy pain management, approximately 80% respondents reported using epidural analgesia, with over 90% recommending a combination of a local anesthetic drug and opioids.20


Figure 24–2. Multimodal analgesia. Action of analgesics at various sites of the pain pathway. (Modified from Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(13):185-211, with permission from Adis. © Springer International Publishing AG 2007. All rights reserved.)

Table 24–1. Analgesic Options for Management of Acute Post-Thoracotomy Pain


Epidural Analgesia

Thoracic epidural catheterization is typically performed at mid-thoracic levels before induction of anesthesia. The paramedian approach to the epidural space is often the recommended technique because the obliquity of thoracic spinous processes makes the midline approach potentially difficult. Either a “loss of resistance” technique or “hanging drop” method may be used to identify the epidural space.

Most anesthesiologists are experienced with placement of lumbar epidural catheters using a “loss of resistance” technique. Although there are anatomic differences between the thoracic and lumbar spine, the fundamental technique of epidural space identification is consistent. Therefore, use of “loss of resistance” for placement of thoracic epidural catheters capitalizes on the anesthesiologist’s technical experience and knowledge.

“Hanging drop” technique entails placing a small amount of saline in the hub of the epidural needle after the stylet has been withdrawn. Upon entering the epidural space, negative pressure causes the meniscus of the fluid to disappear into the hub of the epidural needle. There is debate about whether the negative pressure created with the “hanging drop” technique is secondary to negative intrathoracic pressure, tenting of the dura with needle advancement, or both. The authors find the “hanging drop” technique performed in the sitting position particularly useful when working with trainees: withdrawal of fluid into the hub of the epidural needle provides an unambiguous visual end-point for the supervising physician.

Thoracic epidural local anesthetic administration has been shown to reduce lower extremity motor block as compared with lumbar placement.21 Additionally, given that the site of epidural needle/catheter placement determines the distribution pattern of neural blockade, there is a considerable theoretical advantage for thoracic catheter placement with a thoracic incision.22,23 Common adverse effects and complications of epidural analgesia include dural puncture, post-dural puncture headache, excessive motor blockade, and unsuccessful placement. Uncommon complications include epidural abscess, nerve injury, epidural hematoma, and paraplegia. Epidural analgesia is generally contraindicated in patients who are anticoagulated, septic, or have evidence of infection at the intended site of epidural placement. Guidelines for the management of epidural analgesia in the setting of anticoagulation are included in Table 24-2. Thoracic epidural catheter placement is often considered to be significantly riskier than insertion at the lumbar spine level due to concerns for possible spinal cord injury; evidence does not support this perceived increased risk.24,25

Table 24–2. Suggested Guidelines for Epidural Analgesia and Anticoagulation


Continuous infusion of local anesthetic and/or opioid into the epidural space is commonly used in the acute postoperative management of thoracic surgery patients. Compared with intravenous opioids, patients with epidural analgesia have superior pain control, less respiratory depression, and fewer pulmonary complications.26-28 In a comparative study of thoracic epidural analgesia versus systemic analgesia (PCA), there were well-demonstrated improvements in analgesia and quality of life in patients receiving epidurals.29 Investigations have not shown a dramatic difference in analgesia between the thoracic and lumbar route when opioid alone is used for epidural administration.30-32 Modest improvements in analgesic potency and clinical outcomes have been demonstrated with thoracic versus lumbar epidural administration of combined opioid and local anesthetic.27,28 The procedure-specific postoperative pain management (PROSPECT) working group recommends thoracic epidural or paravertebral blocks as first-line analgesic methods.33

A wide variety of opioids have been used in epidural analgesic regimens. The hydrophilic opioids morphine and hydromorphone have been shown to have similar efficacy when compared to postoperative analgesia.34 Hydromorphone has a favorable side effect profile with less respiratory depression, pruritus, and urinary retention when compared with morphine.35 Thoracic epidural administration of the hydrophobic opioid fentanyl was initially considered to have the advantage of segmental spinal analgesia, as this phenomenon is present during bolus administration. However, during continuous administration the analgesic effect of epidural fentanyl appears largely due to systemic absorption.36,37 The predominantly systemic distribution of epidural fentanyl infusion potentially makes this drug less desirable when other options are available. Nonetheless, patients with a history of pruritus, nausea, and other side effects with hydrophilic opioids such as morphine and hydromorphone may benefit from the choice of this lipophilic drug.38

Epidural administration of local anesthetic improves analgesia, but may produce sympathetic blockade, bradycardia, peripheral vasodilation, and hypotension. Sympathetic blockade is greater with thoracic epidural catheters than with lumbar epidural catheters,39 although it rarely requires removal of the local anesthetic from the infusion. The combination of epidural local anesthetic and opioid is noted to provide superior analgesia and reduction of side effects when compared with either drug class alone.40,41 Additionally, epidural local anesthetics have been shown to improve oxygenation and reduce pulmonary complications when compared with systemic analgesics (Table 24-3).26

Table 24–3. Drugs Used in Continuous Thoracic Epidural Analgesia


Patient controlled epidural analgesia (PCEA) has also been used in the delivery of thoracic epidural analgesia, and provides the ability to deliver effective analgesia with reduced opioid and local anesthetic doses.21,42 The advent of PCEA offers the promise of improved analgesia and patient satisfaction.43 PCEA has been shown to improve pain scores and cough as compared with continuous epidural analgesia and systemic analgesia.44 It allows patients to control pain by administering a bolus dose of local anesthetic and opioid mixture according to their individual need, tailoring the drug requirements to their activity level.45 A recent survey of PCEA with bupivacaine and hydromorphone demonstrated good analgesia without significant side effects in orthopedic patients.46 Although the literature regarding PCEA use for thoracic surgery is more limited, the side effect profile seems comparable to that of the lumbar space.47,48 The recommended dosing schedule for PCEA is included inTable 24-4.

Table 24–4. Recommended Dosing Schedule for PCEA


In patients with poorly controlled pain, the use of clonidine may be considered. Epidural clonidine (0.2-0.5 μg/kg/h) may improve symptom control, especially in patients with preexisting chronic pain states.49 Clonidine, an alpha-2 receptor agonist, has been found to provide analgesia, especially in neuropathic pain states.50 It appears to have analgesic activity in the periphery, the spinal cord dorsal horn, and the brainstem. Clonidine’s analgesic mechanism of action appears to predominantly involve spinal cholinergic activation and hyperpolarization of the primary afferent neuron.49,51 While it may be quite effective in potentiating epidural opioid analgesia, dosing may be limited by bradycardia, hypotension, and sedation.52

Ketamine has also been used in the epidural space to potentiate the analgesic effect of opioids53-55; however, its safety in the neuraxis needs to be established prior to recommending it for clinical use. Current scientific evidence supports the use of ketamine as an intravenous infusion for patients with preoperative opioid tolerance. A loading dose of 0.5 mg/kg on induction of anesthesia and a continuous infusion of 10 μg/kg/min during surgery and terminated at wound closure has been shown to significantly reduce morphine consumption at 24 and 48 hours as well at 6 weeks postoperatively in this population.56

Thoracic Paravertebral Blockade

Paravertebral blockade (PVB) is an alternative analgesic technique to thoracic epidural placement. Studies comparing surgically placed paravertebral catheters with thoracic epidural catheters have demonstrated similar analgesic benefit after thoracic surgery with a better side effect profile with paravertebral catheterization.57,58 Research involving percutaneously placed paravertebral catheters has been more limited to date, although there appears to be a similar analgesic result when this approach is compared with the surgically performed approach.59 The technique was first introduced in the early 1900s for analgesia following abdominal surgery; it was not until the 1970s that paravertebral blockade was commonly used for thoracotomies.60 It is well suited for treating post-thoracotomy pain because of the unilateral action of the paravertebral blocks. While single-shot injections performed at multiple levels may provide adequate analgesia, given the limited duration of analgesia obtained, catheter placement and continuous infusion may be preferable.


The thoracic paravertebral space (PVS) is a wedge-shaped space that lies on each side of the vertebral column (Figure 24-3). Paravertebral blockade involves injection of local anesthetic in the vicinity of each spinal nerve root within the paravertebral space, resulting in unilateral anesthesia for thoracic surgery. The PVS connects medially with the epidural space via the intervertebral foramen and laterally with the intercostal space. The injectate may migrate to these spaces, but the magnitude of spread is unpredictable. On rare occasions, if the dural sleeve around the spinal nerve is inadvertently entered during the procedure, a subarachnoid injection may result. Injectate also frequently spreads both superiorly and inferiorly within the paravertebral space. While the spinal nerves course through the PVS as they exit the spinal canal, the sympathetic chain traverses the space anteriorly. The intercostal arteries, hemiazygos veins and lymphatics also pass through the PVS.


Figure 24–3. Transverse section of the thoracic spine depicting the boundaries, contents and structures surrounding the paravertebral space.

For thoracotomy, the levels blocked are usually between T4 and T9 when single-shot injection technique is used. Care must be exercised when counting the vertebrae before injection. Because of the steep angulations of the thoracic spinous processes, the tip of one spinous process corresponds to the transverse process and PVS of the vertebrae below (ie, T5 spinous process corresponds to T6 transverse process (Figure 24-4A and B). The thoracic transverse processes project laterally a mean distance of 3 cm from the midline. The needle should therefore be inserted 2½ cm lateral to the spinous process at each level. The mean depth from the skin to the PVS is 5.5 cm.


Figure 24–4. Landmarks for paravertebral block. A. Surface landmarks. The needle should be inserted 2½ cm lateral to the spinous process of each level to be blocked. B. Bony structure of the thoracic spine and ribcage. Note the steep angulations of the thoracic spinous processes. The tip of one spinous process corresponds to the transverse process and paravertebral space of the vertebra below. (Only part A reproduced with permission from Hadzic A: The New York School of Regional Anesthesia Textbook of Regional Anesthesia and Acute Pain Management. McGraw-Hill, Inc. 2007. Figure 43-6.)

For single-shot injection, the sites are labeled, the skin cleansed, and a 20-gauge Tuohy needle is advanced, seeking contact with the transverse process. The needle is then withdrawn and redirected caudally, advancing about 1 cm further than the distance to the transverse process until a tactile “pop” is noted as the needle passes through the costotransverse ligament into the PVS. Alternatively, a nerve stimulation technique (0.5-0.6 mA) is used to identify contraction of intercostal muscles as a result of spinal nerve stimulation. Three to four milliliters of local anesthetic (eg, 0.5% ropivacaine with 1:400,000 epinephrine) are administered after careful aspiration. The total volume of local anesthetic injected should be kept below the toxic dose when multiple injections are performed.

Continuous PVB can be instituted either by threading a catheter through an epidural needle after an initial bolus dose of local anesthetic or by placement of a catheter under direct vision by the surgeon.61Various infusions have been used for paravertebral catheters; the reduced severity of sympathectomy often seen with the paravertebral technique may allow the use of more concentrated local anesthetics than are tolerable in the epidural space.58

The contraindications for PVB are similar to other regional anesthetic techniques and include local skin infection, coagulopathy, and hemodynamic instability.


The most common adverse event reported is technical failure. The published incidence of block failure ranges between 6% and 11%.62,63 Block failure consists of inability to provide adequate analgesia. Unintentional vascular puncture can occur in PVBs and should be recognized before injection of local anesthetic. Other common side effects of PVBs are mild hypotension, hematoma, or pain at the site of injection. Unintentional pleural puncture and consequent pneumothorax can occur with deep insertion of the needle. Therefore, it is necessary to watch for aspiration of air and/or cough during needle insertion. In a small proportion of patients, epidural spread of injectate can occur.

Intercostal Nerve Blockade

Intercostal nerve blockade is another regional approach for analgesia following thoracotomy. It can be performed percutaneously prior to surgery or by the surgeon under direct vision prior to closure of the incision. Prior to surgery, the block can be administered as a single injection, multiple injections, or continuously via an indwelling intercostal catheter.64 Due to the high levels of systemic vascular absorption, intercostal blockade achieves the highest blood levels of local anesthetic per volume injected of any block in the body. Therefore, particular attention must be given to the risk of local anesthetic toxicity. It is generally believed that intercostal blocks and catheters do not provide analgesia as effectively as thoracic epidural catheter infusions.65 However, improved analgesia may be obtained when the catheter is placed under direct surgical exposure to cover several intercostal spaces.66


The intercostal nerve is located in the neurovascular bundle at the lower border of each rib (Figure 24-5). The percutaneous block can be performed with the patient in the lateral, sitting, or prone position. The patient’s ribs are palpated and the block is performed approximately 6 to 8 cm lateral to the spinous process. A small gauge needle, eg, (22-25 gauge) is inserted 2 to 4 mm beneath the inferior border of the rib with a cephalic angle of 20 degrees in order to reach the subcostal groove. Following negative aspiration, 2 to 5 mL of local anesthetic is injected. Although pneumothorax is a potential complication, its incidence is rare despite the close proximity of the lung and pleura to the injection site.67 With multiple injections, caution should be exercised not to exceed the total allowable local anesthetic volume.


Figure 24–5. Location of the intercostal neurovascular bundle.

Interpleural Block

Interpleural blockade is a technique wherein local anesthetic is injected between the parietal and visceral pleura, allowing local anesthetic to diffuse through the former to produce ipsilateral blockade of multiple thoracic dermatomes. This technique may be useful in patients for whom epidural analgesia is contraindicated or technically challenging. Although interpleural blockade has not been widely adopted by physicians, the proponents of this technique have demonstrated effective analgesia with a low incidence of complications; nonetheless, patients who undergo interpleural analgesia frequently require supplemental opioids.68 In the treatment of post-thoracotomy pain, interpleural analgesia has been found to be inferior to other techniques such as epidural or paravertebral catheterization.33

The interpleural space is 10 to 20 microns in width, has a surface area of 2000 cm2 in a 70-kg man, and a static volume of approximately 0.1 to 0.2 mL/kg.69 Cadaver studies have demonstrated that interpleurally injected dye diffuses through the parietal pleura to the subpleural space and backwards to multiple intercostal nerves, and that the dye tends to pool in the interpleural paravertebral area.69

A significant amount of local anesthetic can be absorbed by the visceral pleura, offsetting the effectiveness of the drug administered in the interpleural space. The rapidity of absorption can be altered by the presence of inflammation, disease, or trauma to the thoracic cavity. While interpleural analgesia has been advocated after thoracotomy, satisfactory results are often elusive. Reasons why interpleural block may be ineffective for post-thoracotomy pain include uneven distribution of local anesthetic within the disrupted pleural cavity, loss of local anesthetic through chest tube drainage, and binding of local anesthetic to proteins in the surgical effusion.70


The key to successful interpleural block is identification of the interpleural space by detection of negative pressure. Negative interpleural pressure may be identified using different techniques: passive suction of an air- or fluid-filled syringe, a falling column of fluid, or by electronic devices.71-74 It is recommended that the block be performed in the lateral position and the needle be inserted approximately 8 to 10 cm lateral from the dorsal midline.75 Using sterile technique, the needle insertion site is infiltrated with local anesthetic. A Tuohy needle is placed into the interpleural space using one of the above referenced methods. A standard epidural catheter is then threaded approximately 5 to 10 cm into the interpleural space.

Analgesia has also been obtained by injecting 20 mL of 0.5% bupivacaine with epinephrine (5 μg/mL) every 8 hours into the pleural cavity using the chest drains in patients with tube thoracostomies for spontaneous pneumothorax. The duration of analgesia can last up to 4 hours.76

There are several contraindications to the use of this procedure, including the presence of pleural effusions, inflammation, fibrosis, bronchopleural fistula, and empyema. Complications related to interpleural block include pneumothorax, pleural effusion, Horner’s syndrome and catheter-related problems such as displacement and loss. For a more extensive discussion of interpleural analgesia, the reader is directed to the 2-part review by Dravid et al.70,75

Multimodal Analgesia

Multimodal analgesia utilizes a combination of analgesics with different mechanisms of action. The use of local anesthetic infiltration, nonsteroidal anti-inflammatory agents, acetaminophen, and/or gabapentinoids has been demonstrated to reduce postoperative opioid consumption and opioid-related side-effects.77-80 For patients with inadequate analgesia despite the use of a regional anesthetic technique, adjuvant analgesics should be considered. The multimodal approach may optimize analgesia and minimize the risks of sedation and respiratory depression.81

The ultimate goal of multimodal therapy is one of preventive analgesia—reducing perioperative pain sensitization with the intention of reducing the incidence or severity of acute and chronic pain states.82 Although the longer-term benefits of prolonged local anesthetic nerve blockade have been questioned,83,84 the use of systemic analgesics such as ketamine has been shown to improve pain scores and outcomes up to 6 months postoperatively.85

NSAIDs have demonstrated significant advantages in the perioperative period because of their opioid-sparing effects, but are not without their limitations and toxicities. Cyclooxygenase-2 (COX-2) selective inhibitors were developed with the hope to minimize the potential side-effects of non-selective NSAIDS.86 COX-2 inhibitors have been shown to reduce the incidence of side effects such as gastrointestinal ulceration, bleeding tendencies and renal dysfunction that are common to nonspecific COX inhibition. Unfortunately, the reduction in gastrointestinal side effects has been associated with prothrombotic activity resulting in increased cardiac risk profile.87-89

Other drugs that have been used as part of a multimodal regimen include the alpha-2 agonists dexmedetomidine and clonidine. As discussed earlier, epidural clonidine is commonly used along with local anesthetics and/or opioids to improve the quality of analgesia.90 Side effects such as bradycardia and hypotension can be minimized by carefully monitoring the dose. The more selective alpha-2 agonist dexmedetomidine91 has analgesic activity at both spinal and supraspinal sites, and has been used as analgesic adjunct with minimal adverse effects.


Characteristics and Incidence

Thoracotomy, like amputation surgery, carries a high risk for the development of persistent postoperative pain. Chronic post-thoracotomy pain (CPTP) was first noted in 1944 during World War II in men who had undergone a thoracotomy for chest trauma.92 Prior to the 1990s, CPTP was considered to be transient, lasting weeks to months, and was frequently attributed to recurrent malignant disease.93 It was not until the 1991 that CPTP was described in the medical literature as a discrete entity, distinguishing it from disease recurrence.94

The International Association for the Study of Pain (IASP) defines CPTP as “chronic dysesthetic burning and aching pain that recurs or persists along a thoracotomy scar at least 2 months following a surgical procedure.” It is generally considered a postoperative neuropathic pain. Other conditions causing thoracic pain, such as post-herpetic neuralgia, a thoracic herniated disc, or intercostal neuralgia from another source (ie, rib fracture, vertebral compression fracture) should be considered in the treatment plan, as the characteristics of pain are dependent upon the underlying pathophysiologic mechanisms. Patients in whom pain is caused by cancer usually present with costopleural syndrome of moderate to severe intensity. Pain in CPTP can be localized to the chest wall or along the scar and is usually associated with dysesthesia and allodynia in a segmental distribution. These symptoms are commonly exacerbated by temperature changes, touch, and shoulder motion. In a small group of patients, pain can be caused by a traumatic neuroma. This pain is burning and lancinating, with a positive Tinel’s sign. CPTP patients, especially the elderly, may also display restriction in ipsilateral shoulder movement. The pain is oftentimes severe enough to limit daily functioning long after the procedure.95 Some patients might even develop signs and symptoms of complex regional pain syndrome in the ipsilateral upper limb.

Etiology and Risk Factors

Patients who undergo a thoracotomy procedure often have postoperative pain accompanied by sensory loss in the distribution of the associated intercostal nerve, implying some degree of neural injury. The incidence of chronic postsurgical pain reported in the literature is anywhere from 5% to 70% depending on the type of surgery13,15 (Table 24-5). Incidence of CPTP appears to be highly variable, but the literature reveals that up to 60% patients report persistent pain a month after surgery33 and 30% to 50% patients have pain at 1 or 2 years. In a smaller percentage (3%-5%), this pain is severe in nature. However, true assessment of the impact of severe post-thoracotomy pain is difficult, as many patients do not seek medical help for their pain, declaring it only upon questioning.96

Table 24–5. Incidence of Persistent Postoperative Pain after Various Surgical Procedures


Apart from the surgical procedure itself, there are a number of other possible risk factors that have been elucidated for the development of CPTP. These include age, gender, genetics, severity of preoperative pain, type of surgery, a cancer diagnosis, radiation treatment, chemotherapy, and psychosocial factors. Additionally, patients with intense acute postoperative pain have an increased incidence and severity of CPTP, supporting the importance of the perioperative analgesic regimen in the prevention of chronic post-thoracotomy pain.103 Katz et al9 found that acute postoperative within the first 24 hours was the only factor that predicted the presence of long-term pain. This concept was further supported by a study of 250 thoracotomy patients demonstrating that severe acute pain was more likely to develop into persistent postoperative pain.104


Sensitivity to acute pain and its consequences varies between individuals and it has been recognized that genetic factors may contribute to pain perception. Female gender has also been associated with the risk of developing CPTP.105,106 Several candidate genes have been identified, including polymorphism of catechol-o-methyltransferase (COMT) and genetic variants in the voltage gated sodium channels.96The exact role that these polymorphisms play in the predisposition to CPTP is unknown.

It is also well established that psychosocial conditions such as anxiety, depression, malignant disease, and social-economic conditions affect the perception of pain.107 Preexisting chronic pain conditions have also been postulated to predispose patients to the development of CPTP. Keller et al found in their retrospective analysis that 52% users of preoperative analgesics developed CPTP, in contrast to only 5.5% patients who did not use them/preoperative analgesics.3 Perttunen et al95 reported an incidence of preoperative pain of 17% in a group of patients with CPTP, but they did not analyze preoperative pain as an independent risk factor.


The type of surgical intervention also plays a role in CPTP: patients undergoing more extensive surgical procedures (eg, pneumonectomy) are thought to be at higher risk of developing CPTP than those having less extensive procedures (eg, wedge resection). Using this rationale, the less invasive video-assisted thoracoscopic surgery (VATS) was thought to have the potential to reduce acute postoperative pain when compared to open thoracotomy. However, studies have demonstrated that there is no difference in the incidence of CPTP between VATS and open thoracotomy.108-110 VATS is still likely to cause intercostal nerve injury secondary to trauma from trocar insertion and manipulation of instruments.

Rib retraction compresses the intercostal nerve; however, it is believed that closure and approximation of the ribs may be responsible for nerve injury and the development of CPTP. It is reasonable to expect that patients with an injured intercostal nerve would have higher postoperative pain levels and analgesic consumption, and a higher rate of CPTP. Current knowledge of surgical risk factors for CPTP is based entirely on nonrandomized trials and relatively low quality randomized data.4

Muscle-sparing thoracic incisions have also been used to attempt to decrease the incidence of postoperative pain and morbidity. A muscle sparing technique where the serratus anterior and latissimus dorsi muscles are retracted rather than incised was thought/theorized to reduce soft tissue injury and its consequences.111 Unfortunately, this approach has not been shown to be superior to the traditional posterolateral incision.112,113

Management of Chronic Post-Thoracotomy Pain

Recurrence, progression, or metastasis of a malignant tumor should be ruled out prior to treatment. The management of most neuropathic pain is difficult and at times disappointing, emphasizing the importance of preventing this complication. Indeed, the initiation of a preoperative thoracic epidural regimen has been shown to reduce the incidence of CPTP.114 This is consistent with the studies demonstrating an increased risk of CPTP with severe postoperative pain. Aggressive and multimodal analgesic regimens may decrease pain severity, analgesic consumption, and the cascade of neurophysiologic events that can lead to hyperalgesia and allodynia. Combinations of NSAIDs, opioid premedication, and regional anesthesia have been shown to be part of an effective regimen.115,116

Standard treatment of CPTP currently involves antineuropathic therapies such as anticonvulsants, tricyclic antidepressants, and consideration of neural blockade procedures such as intercostal and paravertebral blocks. In refractory cases, these treatments may be combined with complementary techniques such as cognitive behavioral therapy117 and acupuncture.118,119 NMDA receptor modulation with ketamine infusion may be a useful adjunct in conditions of allodynia, hyperalgesia and opioid tolerance (Table 24-6).

Table 24–6. Therapeutic Options for Chronic Post-Thoracotomy Pain (CPTP)



Although our current therapeutic armamentarium is growing, effective treatment of chronic post-thoracotomy pain remains a significant challenge. Indeed, it is best to prevent the cascade of neural sensitization in the perioperative period. Although the use of regional anesthesia and perineural catheters in the prevention of chronic pain following joint replacement has been disappointing to date,83,84there is evidence of decreased chronic pain following thoracotomy with preemptive epidural placement.114 The difference in outcomes may lie in the stronger neuropathic nature of CPTP as compared with post-orthopedic surgery pain. In addition to significant physiologic and psychological consequences of untreated pain, inadequate pain relief can potentially increase the incidence of chronic persistent pain, mandating an aggressive approach to the acute treatment of the thoracic surgical patient. Preemptive thoracic epidural analgesia is considered the gold standard because it provides excellent analgesia and decreases pulmonary complications. When epidural analgesia is contraindicated, other pharmacological approaches combined with paravertebral block should be considered as part of an effective pain management strategy. In addition to regional anesthesia, multimodal techniques including COX-2 inhibitors, gabapentinoids, and acetaminophen should be considered in an effort to maximize analgesia and minimize side effects. In opioid tolerant patients, the NMDA antagonist ketamine may be helpful in the perioperative period.

Although there are medications, procedures, and psychological interventions that may improve the severity of chronic post-thoracotomy pain, results are frequently disappointing. Current knowledge suggests that aggressive management of acute pain may offer the best outcomes for patients undergoing thoracic surgery.


1. Phillips DM. JCAHO pain management standards are unveiled. Joint Commission on Accreditation of Healthcare Organizations. JAMA. 2000;284(4):428-429.

2. Sabanathan S, Eng J, Mearns AJ. Alterations in respiratory mechanics following thoracotomy. J Roy Coll of Surgeons Edinburgh. 1990;35(3):144-150.

3. Keller S, Carp NZ, Levy MN, Rosen SM. Chronic post thoracotomy pain. J Cardiovasc Surg. 1994;35(6 Suppl 1):161-164.

4. Wildgaard K, Ravn J, Kehlet H. Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention. Eur J Cardiothorac Surg. 2009;36:170-180.

5. Kruger M, McRae K. Pain management in cardiothoracic practice. Surg Clin North Am. 1999;79(2):387-400.

6. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology. 1995;82(6):1474-1506.

7. Power I, McCormack JG, Myles PS. Regional anaesthesia and pain management. Anaesthesia. 2010;65(Suppl 1):38-47.

8. Stadler M, Schlander M, Braeckman M, Nguyen T, Boogaerts JG. A cost-utility and cost-effectiveness analysis of an acute pain service. J Clin Anesth. 2004;16(3):159-167.

9. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12(1):50-55.

10. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000;93(4):1123-1133.

11. Li W, Lee RL, Lee TW, Ng CS. The impact of thoracic surgical access on early shoulder function: video-assisted thoracic surgery versus posterolateral thoracotomy. Eur J Cardiothorac Surg. 2003;23(3):390-396.

12. Steegers M, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OH. Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain. 2008;9(10):955-961.

13. Woolf C. Generation of acute pain: central mechanisms. Br Med Bull. 1991;47(3):523-533.

14. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(3):185-211.

15. Thompson S, King AE, Woolf CJ. Activity-dependent changes in rat ventral horn neurons in vitro: summation of prolonged afferent evoked postsynaptic depolarizations produce a d-2-amino-5-phosphonovaleric acid sensitive windup. Eur J Neurosci. 1990;2(7):638-649.

16. Gerner P. Postthoracotomy pain management problems. Anesthesiol Clin. 2008;26(2):355-367.

17. Martinez-Barenys C, Busquets J, de Castro PE, et al. Randomized double-blind comparison of phrenic nerve infiltration and suprascapular nerve block for ipsilateral shoulder pain after thoracic surgery.Eur J Cardiothorac Surg. 2011;40(1):106-112.

18. Danelli G, Berti M, Casati A, et al. Ipsilateral shoulder pain after thoracotomy surgery: a prospective, randomized, double-blind, placebo-controlled evaluation of the efficacy of infiltrating the phrenic nerve with 0.2% wt/vol ropivacaine. Eur J Anaesthesiol. 2007;24(7):596-601.

19. Muehling BM, Halter GL, Schelzig H, et al. Reduction of postoperative pulmonary complications after lung surgery using a fast track clinical pathway. Eur J Cardiothorac Surg. 2008;34(1):174-180.

20. Suwanchinda V, Suksompong, S, Prakanrattana, U, Udompunthurak, S. Epidural analgesia for pain relief in thoracic surgery. J Med Assoc Thai. 2000;83(4):358-363.

21. Liu S, Allen, HW, Olsson, GL. Patient-controlled epidural analgesia with bupivacaine and fentanyl on hospital wards: prospective experience with 1,030 surgical patients. Anesthesiology. 1998;88(3):688-695.

22. Visser WA, Lee RA, Gielen MJ. Factors affecting the distribution of neural blockade by local anesthetics in epidural anesthesia and a comparison of lumbar versus thoracic epidural anesthesia. Anesth Analg. 2008;107(2):708-721.

23. Visser WA, Liem TH, van Egmond J, Gielen MJ. Extension of sensory blockade after thoracic epidural administration of a test dose of lidocaine at three different levels. Anesth Analg. 1998;86(2):332-335.

24. Giebler R, Scherer RU, Peters J. Incidence of neurologic complications related to thoracic epidural catheterization. Anesthesiology. 1997;86(1):55-63.

25. Tanaka K, Watanabe R, Harada T, Dan K. Extensive application of epidural anesthesia and analgesia in a university hospital: incidence of complications related to technique. Reg Anesth. 1993;18(1):34-38.

26. Ballantyne JC, Carr DB, deFerranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg. 1998 86(3):598-612.

27. Hurford WE, Dutton RP, Alfille PH, Clement D, Wilson RS. Comparison of thoracic and lumbar epidural infusions of bupivacaine and fentanyl for post-thoracotomy analgesia. J Cardiothorac Vasc Anesth. 1993;7(5):521-525.

28. Kahn L, Baxter FJ, Dauphin A, et al. A comparison of thoracic and lumbar epidural techniques for post-thoracoabdominal esophagectomy analgesia. Can J Anaesth. 1999;46(5 Pt 1):415-422.

29. Ali M, Winter DC, Hanly AM, O’Hagan C, Keaveny J, Broe P. Prospective, randomized, controlled trial of thoracic epidural or patient-controlled opiate analgesia on perioperative quality of life. Br J Anaesth. 2010;104(3):292-297.

30. Guinard JP, Mavrocordatos P, Chiolero R, Carpenter RL. A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy. Anesthesiology. 1992;77(6):1108-1115.

31. Coe A, Sarginson R, Smith MW, Donnelly RJ, Russell GN. Pain following thoracotomy. A randomised, double-blind comparison of lumbar versus thoracic epidural fentanyl. Anaesthesia. 1991;46(11):918-921.

32. Larsen VH, Iversen AD, Christensen P, Andersen PK. Postoperative pain treatment after upper abdominal surgery with epidural morphine at thoracic or lumbar level. Acta Anaesthesiol Scand. 1985;29(6):566-571.

33. Joshi GP, Bonnet F, Shah R, et al. A systematic review of randomized trials evaluating regional techniques for postthoracotomy analgesia. Anesth analg. 2008;107(3):1026-1040.

34. Halpern SH, Arellano R, Preston R, et al. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth. 1996;43(6):595-598.

35. Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Paediatr Anaesth. 1999;9(5):419-422.

36. Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl in humans: the difference between infusion and bolus administration. Anesth Analg. 2003;97(5):1428-1438.

37. Glass PS, Estok P, Ginsberg B, Goldberg JS, Sladen RN. Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl administration. Anesth Analg. 1992;74(3):345-351.

38. White MJ, Berghausen EJ, Dumont SW, et al. Side effects during continuous epidural infusion of morphine and fentanyl. Can J Anaesth. 1992;39(6):576-582.

39. Kortgen A, Silomon M, Pape-Becker C, Buchinger H, Grundmann U, Bauer M. Thoracic but not lumbar epidural anaesthesia increases liver blood flow after major abdominal surgery. Eur J Anaesthesiol. 2009;26(2):111-116.

40. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103(5):1079-1088; quiz 1109-1010.

41. Kopacz D, Sharrock, NE, Allen, HW. A comparison of levobupivacaine 0.125%, fentanyl 4 microg/mL, or their combination for patient-controlled epidural analgesia after major orthopedic surgery.Anesth Analg. 1999;89(6):1497-1503.

42. van der Vyver M, Halpern S, Joseph G. Patient-controlled epidural analgesia versus continuous infusion for labour analgesia: a meta-analysis. Br J Anaesth. 2002;89(3):459-465.

43. Saeki H, Ishimura H, Higashi H, et al. Postoperative management using intensive patient-controlled epidural analgesia and early rehabilitation after an esophagectomy. Surg Today. 2009;39(6):476-480.

44. Kammoun W, Mestiri T, Miraoui W, et al. Patient controlled epidural analgesia: interest in thoracic surgery. Tunis Med. 2008;86(2):144-149.

45. Tan T, Wilson D, Walsh A, Hu P, Power C. Audit of a ward-based patient-controlled epidural analgesia service in Ireland. Ir J Med Sci. 2011;180(2):417-421.

46. Liu SS, Bieltz M, Wukovits B, John RS. Prospective survey of patient-controlled epidural analgesia with bupivacaine and hydromorphone in 3736 postoperative orthopedic patients. Reg Anesth Pain Med. 2010;35(4):351-354.

47. Valairucha S, Maboonvanon P, Napachoti T, Sirivanasandha B, Suraseranuvongse S. Cost-effectiveness of thoracic patient-controlled epidural analgesia using bupivacaine with fentanyl vs bupivacaine with morphine after thoracotomy and upper abdominal surgery. J Med Assoc Thai. 2005;88(7):921-927.

48. Ladak SS, Katznelson R, Muscat M, Sawhney M, Beattie WS, O’Leary G. Incidence of urinary retention in patients with thoracic patient-controlled epidural analgesia (TPCEA) undergoing thoracotomy. Pain Manag Nurs. 2009;10(2):94-98.

49. Eisenach JC, De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;85(3):655-674.

50. Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain. 1995;61(3):391-399.

51. Lavand’homme PM, Eisenach JC. Perioperative administration of the alpha-2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain. 2003;105(1-2):247-254.

52. Curatolo M, Schnider, TW, Petersen-Felix, S, et al. A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia. Anesthesiology. 2000;92(2):325-337.

53. Wong CS, Liaw WJ, Tung CS, Su YF, Ho ST. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth. 1996;21(6):534-541.

54. Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006;105(1):111-119.

55. Subramaniam BS, Subramaniam K, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth analg. 2001;93(5):1321-1326.

56. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639-646.

57. Gulbahar G, Kocer B, Muratli SN, et al. A comparison of epidural and paravertebral catheterisation techniques in post-thoracotomy pain management. Eur J Cardiothorac Surg. 2010;37(2):467-472.

58. Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy—a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2006;96(4):418-426.

59. Garutti I, Gonzalez-Aragoneses F, Biencinto MT, et al. Thoracic paravertebral block after thoracotomy: comparison of three different approaches. Eur J Cardiothorac Surg. 2009;35(5):829-832.

60. Eason M, Wyatt, R. Paravertebral thoracic block-a reappraisal. Anaesthesia. 1979;34(7):638-642.

61. Richardson J, Sabanathan S. Thoracic paravertebral analgesia. Acta Anaesthesiol Scand. 1995;39(8):1005-1015.

62. Pusch F, Freitag H, Weinstabl C, Obwegeser R, Huber E, Wildling E. Single-injection paravertebral block compared to general anaesthesia in breast surgery. Acta Anaesthesiol Scand. 1999;43(7):770-774.

63. Coveney E, Weltz, CR, Greengrass, R. Use of paravertebral block anesthesia in the surgical management of breast cancer: experience in 156 cases. Ann Surg. 1998;227(4):496-501.

64. Richardson J, Sabanathan S. Continuous intercostal bupivacaine. Ann Thorac Surg. 1993;56(3):596.

65. Debreceni G, Molnar Z, Szelig L, Molnar TF. Continuous epidural or intercostal analgesia following thoracotomy: a prospective randomized double-blind clinical trial. Acta Anaesthesiol Scand. 2003;47(9):1091-1095.

66. Luketich JD, Land SR, Sullivan EA, et al. Thoracic epidural versus intercostal nerve catheter plus patient-controlled analgesia: a randomized study. Ann Thorac Surg. 2005 Jun;79(6):1845-1849; discussion 1849-1850.

67. Moore D. Intercostal nerve block for postoperaive somatic pain following surgery of thorax and upper abdomen. Br J Anaesth. 1975;47(Suppl):284-286.

68. Bachmann-Mennenga B, Biscoping J, Kuhn DF, et al. Intercostal nerve block, interpleural analgesia, thoracic epidural block or systemic opioid application for pain relief after thoracotomy? Eur J Cardio-Thorac Surg. 1993;7(1):12-18.

69. McKenzie AG, Mathe S. Interpleural local anaesthesia: anatomical basis for mechanism of action. Br J Anaesth. 1996;76(2):297-299.

70. Dravid RM, Paul RE. Interpleural block - part 2Anaesthesia. 2007;62(11):1143-1153.

71. Weston S, Clark I. Intrapleural catheter placement. Anaesth Intensive Care. 1990;18(1):140.

72. Ben-David B, Lee E. The falling column: a new technique for interpleural catheter placement. Anesth Analg. 1990;71(2):212.

73. Lee E, Ben-David B. Identification of the interpleural space. Br J Anaesth. 1991;67(130).

74. Kvalheim L, Reiestad, F. Interpleural catheter in the management of postoperative pain. Anesthesiology. 1984;61(A231).

75. Dravid RM, Paul RE. Interpleural block - part 1Anaesthesia. 2007;62(10):1039-1049.

76. Engdahl O, Boe J, Sandstedt S. Interpleural bupivacaine for analgesia during chest drainage treatment for pneumothorax. A randomized double-blind study. Acta Anaesthesiol Scand. 1993;37(2):149-153.

77. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5):588-593.

78. Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial.Anesth Analg. 2010;110(1):199-207.

79. Wenk M, Schug SA. Perioperative pain management after thoracotomy. Curr Opin Anaesthesiol. 2011;24(1):8-12.

80. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth. 2011;106(3):292-297.

81. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3):458-462.

82. Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol. 2006;19(5):551-555.

83. Ilfeld BM, Ball ST, Gearen PF, et al. Health-related quality of life after hip arthroplasty with and without an extended-duration continuous posterior lumbar plexus nerve block: a prospective, 1-year follow-up of a randomized, triple-masked, placebo-controlled study. Anesth Analg. 2009;109(2):586-591.

84. Ilfeld BM, Meyer RS, Le LT, et al. Health-related quality of life after tricompartment knee arthroplasty with and without an extended-duration continuous femoral nerve block: a prospective, 1-year follow-up of a randomized, triple-masked, placebo-controlled study. Anesth Analg. 2009;108(4):1320-1325.

85. Remerand F, Le Tendre C, Baud A, et al. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anesth Analg. 2009;109(6):1963-1971.

86. Goldstein JL, Eisen GM, Agrawal N, Stenson WF, Kent JD, Verburg KM. Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib. Aliment Pharmacol Ther. 2004;20(5):527-538.

87. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.

88. Ross JS, Madigan D, Konstam MA, Egilman DS, Krumholz HM. Persistence of cardiovascular risk after rofecoxib discontinuation. Arch Intern Med. 2010;170(22):2035-2036.

89. Salinas G RU, Uretsky BF, Birnbaum Y. The cycloxygenase 2 (COX-2) story: it’s time to explain, not inflame. J Cardiovasc Pharmacol Ther. 2007;12(2):98-111.

90. El-Hennawy AM A-EA, Abd-Elmaksoud AM, El-Ozairy HS, Boulis SR. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. Br J Anaesth. 2009;103(2):268-274.

91. Congedo E, Sgreccia M, De Cosmo G. New drugs for epidural analgesia. Curr Drug Targets. 2009;10(8):696-706.

92. Blades B, Dugan, DJ. War wounds of the chest observed at the Thoracic Surgery Centre. J Thorac Surg. 1944;13:294-306.

93. Kanner R, Martini N. Nature and incidence of post-thoracotomy pain. Proc Am Soc Clin Oncol. 1982;1:152.

94. Dajczman E, Gordon A, Kreisman H, Wolkove N. Long-term postthoracotomy pain. Chest. 1991;99(2):270-274.

95. Perttunen K, Tasmuth T, Kalso E. Chronic pain after thoracic surgery: a follow-up study. Acta Anaesthesiol Scand. 1999;43(3):563-567.

96. Shaw A, Keefe FJ. Genetic and environmental determinants of postthoracotomy pain syndrome. Curr Opin Anaesthesiol. 2008;21(1):8-11.

97. Nikolajsen L, Brandsborg B, Lucht U, Jensen TS, Kehlet H. Chronic pain following total hip arthroplasty: a nationwide questionnaire study. Acta Anaesthesiol Scand. 2006;50(4):495-500.

98. Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS. Chronic pain after hysterectomy. Acta Anaesthesiol Scand. 2008;52(3):327-331.

99. Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H. Chronic pain following Caesarean section. Acta Anaesthesiol Scand. 2004;48(1):111-116.

100. Aasvang E, Kehlet H. Chronic postoperative pain: the case of inguinal herniorrhaphy. Br J Anaesth. 2005;95(1):69-76.

101. Meyerson J, Thelin S, Gordh T, Karlsten R. The incidence of chronic post-sternotomy pain after cardiac surgery—a prospective study. Acta Anaesthesiol Scand. 2001;45(8):940-944.

102. Puolakka PAE, Rorarius MGF, Roviola M, Puolakka TJS, Nordhausen K, Lindgren L. Persistent pain following knee arthroplasty. Eur J Anaesthesiol. 2010;27(5):455-460.

103. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain. 2008;138(1):22-28.

104. Pluijms W, Steegers MA, Verhagen AF. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiologica Scand. 2006;50(7):804-808.

105. Ochroch E, Gottschalk A, Troxel AB, Farrar JT. Women suffer more short- and long-term pain than men after major thoracotomy. Clin J Pain. 2006;22(5):491-498.

106. Gotoda Y, Kambara N, Sakai T, Kishi Y, Kodama K, Koyama T. The morbidity, time course and predictive factors for persistent post-thoracotomy pain. Eur J Pain. 2001;5(1):89-96.

107. Taenzer P, Melzack R, Jeans ME. Influence of psychological factors on postoperative pain, mood and analgesic requirements. Pain. 1986;24(3):331-342.

108. Landreneau R, Mack MJ, Hazelrigg SR, et al. Prevalence of chronic pain after pulmonary resection by thoracotomy or video-assisted thoracic surgery. J Thorac Cardiovasc Surg. 1994;107(4):1079-1085.

109. Kirby T, Mack MJ, Landreneau RJ Rice, TW. Lobectomy—video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial. J Thorac Cardiovasc Surg. 1995;109(5):997-1001.

110. Furrer M, Rechsteiner R, Eigenmann V, Signer C, Althaus U, Ris HB. Thoracotomy and thoracos-copy: postoperative pulmonary function, pain and chest wall complaints. Eur J Cardiothorac Surg. 1997;12(1):82-87.

111. Khan I, McManus KG, McCraith A, McGuigan JA. Muscle sparing thoracotomy: a biomechanical analysis confirms preservation of muscle strength but no improvement in wound discomfort. Eur J Cardiothorac Surg. 2000;18(6):656-661.

112. Ochroch E, Gottschalk A, Augoustides JG, Aukburg SJ, Kaiser LR, Shrager JB. Pain and physical function are similar following axillary, muscle-sparing vs posterolateral thoracotomy. Chest. 2005;128(4):2664-2670.

113. Landreneau R, Pigula F, Luketich et al. Acute and chronic morbidity differences between muscle-sparing and standard lateral thoracotomies. J Thorac Cardiovasc Surg. 1996;112(5):1346-1350.

114. Senturk M, Ozcan PE. The effects of three different analgesia techniques on long-term postthoracotomy pain. Anesth Analg. 2002;94(1):11-15.

115. Doyle E, Bowler GM. Pre-emptive effect of multimodal analgesia in thoracic surgery. Br J Anaesth. 1998;80(2):147-151.

116. Richardson J, Sabanathan S, Mearns AJ, Evans CS, Bembridge J, Fairbrass M. Efficacy of pre-emptive analgesia and continuous extrapleural intercostal nerve block on post-thoracotomy pain and pulmonary mechanics. J Cardiovasc Surg. 1994;35(3):219-228.

117. Naylor M, Naud S, Keefe FJ, Helzer JE. Therapeutic interactive voice response (TIVR) to reduce analgesic medication use for chronic pain management. J Pain. 2010;11(12):1410-1419.

118. Deng G, Rusch V, Vickers A, et al. Randomized controlled trial of a special acupuncture technique for pain after thoracotomy. J Thorac Cardiovasc Surg. 2008;136(6):1464-1649.

119. Vickers A, Rusch VW, Malhotra VT, Downey RJ, Cassileth BR. Acupuncture is a feasible treatment for post-thoracotomy pain: results of a prospective pilot trial. BMC Anesthesiol. 2006;3(6:5).