**1. Introduction**

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postoperative pulmonary function in patients undergoing lung resection. *Chest*,

Post-thoracotomy pain is one of the most severe and long lasting complications after surgery (1-4) which acutely contributes to limit normal respiratory activity impairing the sputum clearance and reducing ventilatory function (5). Along with limb amputation, thoracotomy is the surgical procedure with the highest risk of severe and long lasting acute postoperative pain (6).

Moreover, a chronic post thoracotomy pain syndrome (PTPS) may delay the long term rehabilitation, worsening the quality of life because of the associated neuropathic pain even without recurrences of the primary disease (7). Lung cancer still remains the first cause of death for cancer (8) and prompt pulmonary surgery may be the only effective therapeutic strategy. Consequently, an increasing rate of thoracic surgery will be progressively associated with a higher PTPS incidence in the future.

The syndrome was firstly described in 1944 during the II world war when American surgeons reported persistent intercostal pain in soldiers submitted to thoracotomy (9). Until the end of the nineties, pain treatment was mainly based on intravenous opioids and the incidence of PTPS was about 61% one year after surgery (10).

## **2. Definition and incidence**

The International Association for the Study of Pain (IASP) definition of Post Thoracotomy Pain Syndrome is the following: 'Pain that recurs or persists along a thoracotomy scar at least 2 months following surgical procedure' (7).

PTPS incidence between 11 and 80% has been reported in the literature (11-13). This variability is probably related to the setting of retrospective studies, the lack of an homogeneous definition of the severity and duration of the syndrome, the difference in anesthetic and analgesic protocols, the use of different pain evaluation scales and the time of postoperative follow-up. Moreover, the high variability in PTPS incidence may also be explained by the different attitude of patients towards discomfort (14).

#### **3. Pain characteristics after thoracic surgery**

PTPS is mostly described with the typical characteristics of neuropathic pain, often related to the surgical scar, since 82—90% of pain patients recognize the pain trigger directly to the surgical site (1, 10). Pain is primarily described as aching, tender, with numbness and to a lesser degree burning (1, 15); however, PTPS is sometimes described as tingling and pruritus sensation within the thoracic injured area. Finally, thoracic sensory deficits are referred by

Post Thoracotomy Pain Syndrome 393

involved in both inflammation and central sensitization (33). The gamma – amminobutirric acid (GABA) pathway represents the major inhibition system in the CNS. The suppression of this pathway with pharmacological inhibitors is associated with a dose-dependent allodynia (34). GABA receptors level is reduced after peripheral nerve axotomy, maybe because of primary degeneration of afferent neuron terminals on which the receptor is localized. The consequent reduction in GABA activity may play an important role in central sensitization (35). A separate pathway of nociceptive modulation in CNS is the purinergic system, including specifically adenosine. Neuropathic patients show a reduction in adenosine concentration in both circulating blood and CSF, suggesting a concurrent effect of

Finally, the reduced ability of opiates in relieving neuropathic pain is widely accepted but the exact extent of this phenomenon is controversial. The dose response function of opiates seems to be unfavorably shifted to the right (23). This clinical evidence may be explained by loss of peripheral opiate effect, loss of spinal opiate receptors and increased activity in

• Genetic factors: genetic control of pain involves several genes such as catechol-Omethyltransferase (COMT), voltage-gated sodium channels, and GTP cyclohydrolase and tetrahydrobiopterin-related genes which are characterized by high level of

• Psychological factors: anxiety, depression, malignant disease and social status, may play a determinant role in influencing perception and consequences of chronic pain (13, 41, 42). However the relationship between preoperative psychological factors and PTPS

• Preoperative pain and analgesic consumption: the relationship between preoperative pain and analgesic consumption and the development of chronic pain is well established for some kinds of surgery (43, 44). Moreover, assessing the preoperative pain threshold of each patient may be useful to identify risking patients at risk of postoperative pain which may lead to chronification (electrical, heat, cold and pressure tests) (45-49). Unfortunately, the role of pre-surgical pain in PTPS recurrence is still

• Type and extent of surgery (intercostal nerve damage, resection of the chest wall,

Many surgical approaches for thoracic cavity are described: median sternotomy, bilateral transverse thoracosternotomy, posterolateral thoractomy, muscle sparing thoracotomy and

• Intensity and duration of pain during the first postoperative day.

adenosine in the modulation of chronic pain (36).

physiological opioid antagonism system (23).

variability in the population (39, 40).

controversial (13, 45, 50, 51).

**5.2 Perioperative factors are the:** 

pleurectomy and pneumectomy)

**5.2.1 The type and extent of surgery** 

video-assisted thoracoscopy (VATS) (52).

should be investigated with targeted study.

• Female gender (13, 37). • Age under 60 years (37, 38)

**5. Factors influencing the prevalence of PTPS** 

**5.1 Predisposing factors for the development of chronic pain are:** 

patients in terms of sensory loss and hypoesthesia to cold (16, 17). These neuropathic phenomena are principally located within mammary and sub mammary areas and ipsilateral scapular and interscapular regions.

Comparing to acute postoperative pain, PTPS does not specifically influence the respiratory function but may be able to limit daily activities. In other words, differences between acute and chronic pain are more related to the inability to restore the physiological functions of the organism to homeostatic pre-thoracotomy levels (18). Even if the pain intensity is moderate, normal daily activities might be hampered up to 50 % of cases and sleep disorders could be present in the 25% of patients (10); finally, severe pain could be present in 8% and can persist in more than 40% of cases (15). Unfortunately the social consequences and subsequent analgesic use have only been recorded in a minority of studies with different design (4, 13, 15, 19, 20) so that the actual impact of chronic pain on daily life remains undefined.

#### **4. Pathogenetic features**

The mechanisms that lead to PTPS are multiple and the pathogenesis is still unclear. The pathway of the painful experience related to thoracotomy is complex. Inputs from skin, muscles, ribs, and parietal pleura are conducted through intercostal nerves to the dorsal horn. Moreover, the vagus nerve and the autonomic system are involved in the conduction of noxious stimuli from visceral pleura and lung parenchyma; finally, the phrenic nerve is related to noxious stimuli from mediastinum, diaphragm and pericardial pleura (21, 22).

Although the pathogenesis of chronic neuropathic post thoracotomy pain syndrome is complex, the direct damage of intercostal nerves and the consequent effect on pain transmission seems to play a primary role (23). Many important peripheral and central nociceptive adaptions have been described after peripheral nerve injury (23).

Peripherally, ephaptic conduction or "cross-excitation" generated by neurons linked to injured nerves may trigger a distorted pathway of nociceptive stimuli which may be clinically relevant for the ongoing neuropathic pain (23, 24). Moreover, in these neurons the expression of sodium and calcium channels may be altered (23, 25, 26). A collateral sprouting of fibers from sensory axons into denervated areas has been also described in an animal model, but the degree of sprouting was not proportional to the degree of hyperalgesia after nerve section so that the role of this phenomenon seems to be limited (23, 27). Another important role may be played by direct coupling of the sympathic nerve system and the sensory nervous system in the dorsal root gangliation (28). The trigger signal of this sprouting is still unclear but the release of neurotrophic factors and cytokines following wallerian degeneration is likely to be decisive (29).

Central mechanisms are also implicated in the development of this syndrome (23). The nerve injury is coupled to a considerable degree of spinal cord reorganization. Largediameter, low threshold A-beta fibres from mechanoceptors may wrongly sprout into lamina II, which is normally the termination of high-threshold A-delta and C fibres, leading to an erroneous interpretation of nociceptive stimuli (30). Peripheral nerve injury, similarly to chronic inflammation, is coupled to a persistent state of hyperexcitability of the dorsal horn neurons, a process called "central sensitization" (31, 32). The excitatory amino acid glutamate is known to be the major excitatory neurotransmitter related to noxious stimulation. Many postsynaptic receptors are linked to glutamate release but a strong evidence suggests that N-methyl-D-aspartate (NMDA) receptor subtype is the main

patients in terms of sensory loss and hypoesthesia to cold (16, 17). These neuropathic phenomena are principally located within mammary and sub mammary areas and

Comparing to acute postoperative pain, PTPS does not specifically influence the respiratory function but may be able to limit daily activities. In other words, differences between acute and chronic pain are more related to the inability to restore the physiological functions of the organism to homeostatic pre-thoracotomy levels (18). Even if the pain intensity is moderate, normal daily activities might be hampered up to 50 % of cases and sleep disorders could be present in the 25% of patients (10); finally, severe pain could be present in 8% and can persist in more than 40% of cases (15). Unfortunately the social consequences and subsequent analgesic use have only been recorded in a minority of studies with different design (4, 13, 15, 19, 20) so that the actual impact of chronic pain on daily life

The mechanisms that lead to PTPS are multiple and the pathogenesis is still unclear. The pathway of the painful experience related to thoracotomy is complex. Inputs from skin, muscles, ribs, and parietal pleura are conducted through intercostal nerves to the dorsal horn. Moreover, the vagus nerve and the autonomic system are involved in the conduction of noxious stimuli from visceral pleura and lung parenchyma; finally, the phrenic nerve is related to noxious stimuli from mediastinum, diaphragm and pericardial pleura (21, 22). Although the pathogenesis of chronic neuropathic post thoracotomy pain syndrome is complex, the direct damage of intercostal nerves and the consequent effect on pain transmission seems to play a primary role (23). Many important peripheral and central

Peripherally, ephaptic conduction or "cross-excitation" generated by neurons linked to injured nerves may trigger a distorted pathway of nociceptive stimuli which may be clinically relevant for the ongoing neuropathic pain (23, 24). Moreover, in these neurons the expression of sodium and calcium channels may be altered (23, 25, 26). A collateral sprouting of fibers from sensory axons into denervated areas has been also described in an animal model, but the degree of sprouting was not proportional to the degree of hyperalgesia after nerve section so that the role of this phenomenon seems to be limited (23, 27). Another important role may be played by direct coupling of the sympathic nerve system and the sensory nervous system in the dorsal root gangliation (28). The trigger signal of this sprouting is still unclear but the release of neurotrophic factors and cytokines

Central mechanisms are also implicated in the development of this syndrome (23). The nerve injury is coupled to a considerable degree of spinal cord reorganization. Largediameter, low threshold A-beta fibres from mechanoceptors may wrongly sprout into lamina II, which is normally the termination of high-threshold A-delta and C fibres, leading to an erroneous interpretation of nociceptive stimuli (30). Peripheral nerve injury, similarly to chronic inflammation, is coupled to a persistent state of hyperexcitability of the dorsal horn neurons, a process called "central sensitization" (31, 32). The excitatory amino acid glutamate is known to be the major excitatory neurotransmitter related to noxious stimulation. Many postsynaptic receptors are linked to glutamate release but a strong evidence suggests that N-methyl-D-aspartate (NMDA) receptor subtype is the main

nociceptive adaptions have been described after peripheral nerve injury (23).

following wallerian degeneration is likely to be decisive (29).

ipsilateral scapular and interscapular regions.

remains undefined.

**4. Pathogenetic features** 

involved in both inflammation and central sensitization (33). The gamma – amminobutirric acid (GABA) pathway represents the major inhibition system in the CNS. The suppression of this pathway with pharmacological inhibitors is associated with a dose-dependent allodynia (34). GABA receptors level is reduced after peripheral nerve axotomy, maybe because of primary degeneration of afferent neuron terminals on which the receptor is localized. The consequent reduction in GABA activity may play an important role in central sensitization (35). A separate pathway of nociceptive modulation in CNS is the purinergic system, including specifically adenosine. Neuropathic patients show a reduction in adenosine concentration in both circulating blood and CSF, suggesting a concurrent effect of adenosine in the modulation of chronic pain (36).

Finally, the reduced ability of opiates in relieving neuropathic pain is widely accepted but the exact extent of this phenomenon is controversial. The dose response function of opiates seems to be unfavorably shifted to the right (23). This clinical evidence may be explained by loss of peripheral opiate effect, loss of spinal opiate receptors and increased activity in physiological opioid antagonism system (23).
