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


#### **5.2 Perioperative factors are the:**


#### **5.2.1 The type and extent of surgery**

Many surgical approaches for thoracic cavity are described: median sternotomy, bilateral transverse thoracosternotomy, posterolateral thoractomy, muscle sparing thoracotomy and video-assisted thoracoscopy (VATS) (52).

Post Thoracotomy Pain Syndrome 395

The social impact of PTPS as capability to influence daily activites and consequently quality of life were investigated by several studies (4, 10, 13, 15, 20). Commonly the effects of PTPS are registered in the following activities: standing, sitting, getting up, sleep. Even if the pain intensity is moderate, normal daily activities could 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 it's not relieved in more than 40% of cases (50). However, because of lack of right evaluation of this kind of disabilities, the exact impact of PTPS on social field must

Keller et all (57) suggest that relapse of disease can uncontrovertibly rise PTPS incidence. However, even if this data is obvious and well comprehensible, much more data are needed to support this evidence. Moreover, since no data are available about the effects of chemo and radio-therapy on PTPS incidence, several studies must be encouraged to understand

Postoperative analgesia is commonly based on the use of regional anesthesia and systemic drug infusion. Different regional anesthesia techniques have been used: mostly thoracic epidural anesthesia (TEA) (58, 59), thoracic paravertebral block (PVB) (60), and, secondarily, pleural infusion or intercostal nerves block. The role of intrapleural infusion, intercostal nerve block and local infiltration in reducing PTPS is still unclear because studies evaluating

TEA and PVB with opioids and local anesthetics mixture are the most used regional techniques. Nowadays, TEA is still considered the gold standard technique even if PVB has

However the role of TEA in reducing PTPS remains controversial and questionable. In any case, multimodal analgesia using different modalities as regional and systemic analgesic

On the contrary, there is no consensus on the drug to use for adjunct intravenous analgesia. Ketamine has been confirmed as a useful agent (62, 63) while COX-2 inhibitors, celecoxib i.e, were recently proposed as a valid alternative (64). Besides, only few studies reported about the efficacy of the S(+) - isomer of Ketamine (65) that has been demonstrated to have twice the anaesthetic and analgesic potency of the racemic ketamine preparation and is judged to induce less psychic emergence reactions, a reduced number of hallucinations (66) and to be followed by a more rapid recovery of vigilance (67, 68) preserving the hypoxic pulmonary vasoconstriction, enhancing oxygenation and decreasing shunt fractions in monopulmonary

Only few trials have demonstrated the effect of iv ketamine as an adjunct to TEA. Suzuki et al (69) demonstrated the efficacy of 0,05 mg Kg-1 h-1 racemic ketamine combined with TEA with ropivacaine and morphine on acute pain control until 3 months postoperatively but not at 6 months follow-up. Dualé et al (63) confirmed that racemic ketamine (1mg kg-1h-1 during surgery and 1 mg kg-1h-1 in the first 24 hours) was effective in the immediate postoperative

this analgesic technique are confounding and lacking of exhaustive data (45).

**5.3 Postoperative factors 5.3.1 Social consequences** 

be better investigated.

their role on PTPS incidence.

**6.1 Intra and postoperative analgesia** 

**5.3.2 Disease relapse – chemo and radio therapy** 

**6. Prevention and treatment strategies of PTPS** 

recently emerged as valid alternative to TEA (61).

techniques is highly recommended (61).

ventilation (52).

Intercostal nerves are primarily involved in the rib cage pain transmission. The incision of the skin, soft tissue and muscles triggers an inflammatory response. The retraction of the intercostal space, and sometimes the resection of the ribs themselves, increases the damage to the costovertebral and costotrasversal ligaments with the subsequent involvement of the parietal pleura (53).

The intercostal nerve can be compressed by retractors or damaged during rib resection and closure of chest wall or can be trapped by sutures and healing processes. Nociception from mediastinic and diaphragmatic pleura is transmitted by different nervous pathways (phrenic and vagus nerves). This type of pain is deep and poorly localized. Moreover, this painful sensation triggered by diaphragmatic injury is also referred to the homolateral shoulder pain. Pleural drainage also produces deep pain due to both skin incision and pleural irritation.

In addition to surgical injury, the breathing cycle constantly involves the damaged structures, enhancing the trigger of thoracic pain.

The diagnosis of nerve injury is often associated with allodynia and/ or hyperalgesia plus numbness distributed in the area served by affected nerves.

The type of incision is strictly associated to post-thoracotomy pain and damage of intercostal nerves (54). The posterolateral thoracotomy, sparing serratus anterior and trapezius muscles, seems to minimize damaging in intercostal nerves compared to the standard posterolateral thoracotomy. Consequently, this technique is associated with a reduction of pain and improvement mobility of the ipsilateral shoulder in the first seven postoperative days.

However, several studies have questioned these results in terms of both acute and chronic pain after one year. An anterior axillary approach has been proposed to reduce the painful symptoms, but the benefit was not still confirmed by the literature. The technique used for closure of the chest wall may play a role in the intercostal nerve damage.

Nevertheless, all the different surgical approaches described above, may lead either to acute and chronic pain. This finding may be firstly explained by frequent anatomical variants in the intercostal nerves course so that their integrity is not ensured by any surgical choice. Moreover, the surgical retractor, used in all the techniques, may probably play an important role in the damage of the intercostal nerves.

The video-assisted thoracic surgery (VATS) seems to reduce the incidence of PTPS, probably because of multiple small incisions that produce a smaller nerve injury than open thoracotomy. However VATS does not preserve intercostal nerve from damage because the scope may crush nervous fibers against adjacent rib. Moreover the use of retractors to take away the lung section may also damage intercostals nerve (63-27). In conclusion VATS technique does not prevent the PTPS development but seems to reduce the PTPS incidence compared to muscle sparing incision (28)

### **5.2.2 The intensity and duration of pain during the first postoperative day**

Several prospective studies show that the most important predictor for the development of PTPS is the persistent post surgical pain which is strictly related to the severity of acute postoperative pain. Acute postoperative pain, in fact, is related to the amount of intercostal nerves damaged (55, 56). However, some studies found no clear relationship between PTPS and intensity of acute postoperative pain (1, 4, 10). The literature is not exhaustive because no study evaluates overall preoperative, intraoperative and postoperative factors which can influence the incidence of PTPS. Undoubtely, the strict pain control is mandatory in this kind of surgery.
