**6. Factors related to the development of CPOP**

There are different causes that perpetuate CPOP, and there is an argument that places an important relationship of acute severe pain associated with nerve injury as a crucial element of this continuum and subsequently the presence of neuropathic pain. The surgeries that are related with CPOP in this circumstance (nerve injury) are breast reconstruction, thoracotomy, and amputation. It is important to mention that there is not always evidence of nerve damage in patients with CPOP, and those who have nerve damage will not develop CPOP constantly. There is evidence that one of the principal elements of CPOP progression is repeated and intense triggering of primary afferents which encourages peripheral and central sensitization [3, 6, 7].

If the outcome of the surgery is nerve injury the patient will experience inflammatory changes that will encourage electrical discharges and early ectopic events in the nociceptive pathways. There may be observed adjacent propagation of intact nociceptive afferents nearby areas innervated by injured afferents, and this added to changes induced by damage progression in the somatosensorial system developed by this continuum of events posterior to perioperative pain incitement [2, 5]. CPOP progression is defined by neuroplastic changes resulting from neurotrophic factors and the interface neuron-microglia, and in association with the outcomes of inhibitory modulation. If this particular situation is not managed, CPOP can progress and manifest different alterations that can develop a complex pain syndrome that perpetuates over time and the treatment may impose an important challenge [3, 6, 7].

#### **6.1 Chronicity of acute pain**

This event leads to variations in the peripheral and central somatosensory system associated with inflammatory and biochemical modifications that in combination aggravate this pain syndrome. It has been described several changes in distinct receptors where we can punctuate the erratic activation of N-methyl-D-aspartate (NMDA) receptors that leads to liberation of glutamate in the spinal cord at the dorsal horn originated by peripheral afferents, and additionally ectopic and erratic triggering of nerves injured during the surgical event. These neuroplastic changes lead to peripheral and central sensitization resulting in an exaggerated response to pain [3, 6, 9].

Positive symptoms of neuropathic pain include allodynia and hyperalgesia that strongly suggest signs of central sensitization, and these states frequently express incongruence concerning the intensity and perception of the painful stimulus. Hyperalgesia is usually seen throughout the tissue recovery course; if this event persists and it is allowed to progress, it may be related to CPOP progression. Without a doubt, the degree and length of central and peripheral sensitization and the mechanisms causing disparity among the descendent and ascending pain nociceptive pathways; these circumstances fluctuate enormously during the progress of acute severe pain and CPOP [3, 6, 9].

#### **6.2 Animal experiment basic research**

In the 90s of the last century, a specific animal model was designed to recognize mechanisms that are essential for lesion-induced postsurgical pain. A plantar lesion model was described to study particular evidence of the fundamental neurophysiology of lesion-induced pain. Somehow this model describes that many of the mechanisms responsible of pain as inflammation, antigen-induced or neuropathic pain are not responsible for incisional pain and vice versa. A couple of concepts are revealed during an induced lesion, primary hyperalgesia that develops at the side of the incision and subsequently in an area adjacent to the injury when it comes to secondary hyperalgesia after various days once the lesion has established [3, 6, 9].

#### **6.3 Spinal sensitization after surgical incision**

It has been documented that several elements that are used to avert central sensitization and CPOP progression in other pain models were unsuccessfully after surgical incision. The initial reports regarding this model identified that NMDA receptor antagonists were futile in the context of CPOP prevention. Somehow this information guided to the hypothesis that the surgical lesion originates another type of spinal sensitization compared to other pain entities. This type of sensitization is perpetuated after this model (plantar incision) is sustained by the afferent limit of sensitized nociceptors on the non-NMDA/AMPA receptor group, which in conjunction are accountable for no evoked pain and hyperalgesia after surgical lesion. There are several substances responsible of mechanical/heat hyperalgesia that act on the ascending and descending nociceptive pathways, and the stimulation of GABAA and GABAB receptors somehow diminish this response, but there is no evidence on attenuation of no evoked pain by this specific reaction [3, 6, 9].

#### **6.4 Peripheral sensitization after incision**

In the initial stages of surgical lesion, the reports on plantar incision provide substantial evidence of peripheral C and A delta fiber sensitization in the acute phase. There is analysis in behavior and neurophysiological experiments where muscle nociceptors play a crucial function in the cause of no evoked protecting conduct after surgical lesion. Although a skin surgical lesion without involvement of muscle tissue lesion seems to be accountable for promoting mechanical hyperalgesia posterior to surgical lesion. This confirms that a muscle injury is not required for the appearance of positive signs of neuropathic pain on the patient [3, 6, 9].

#### **6.5 Neuroplastic changes in the brain after incision**

Actual evidence confirms that presurgical or postsurgical exposure to distressing elements like immobilization and force swimming test does not make difference on pain awareness to incitements, such as mechanical, hot, and cold, and it somehow delays the period of lesion provoked hyperalgesia after surgical incision. There are reports linked to abolishing stress-induced hyperalgesia by the withdrawal of adrenal gland and impeding the activation of glucocorticoid receptors [3, 6, 9].

#### **7. Prevention of chronic postoperative pain**

As already mentioned, CPOP has a deleterious effect on the quality of life of the person who suffers from it, causing important economic, social and family repercussions. The risk factors that predispose to the presentation of this entity have already been enumerated, and how it can be added to each other for its presentation. That is why efforts should focus on correcting modifiable causes, such as the characteristics of the surgery, anesthesia techniques, and the use of pharmacological prophylaxis [10].

Although it is not a certainty that CPOP can be avoided, diverse reports have determined that the frequency is lower when risk factors are identified [2]. Preoperative factors, such as localized pain far from the surgical site, chronic use of opioids, and mood disorders such as anxiety and depression, will alert about the patients who need multimodal strategies such as regional anesthesia, hyperalgesic drugs, etc. [11]. The objective will then be to reduce the mechanisms of central and peripheral sensitization [12]. Regional anesthesia, peripheral nerve blocks, and intravenous infusions of various anesthetic adjuvants have been shown to be beneficial in the prevention and reduction of chronic postoperative pain [12].

Among the most accepted and recommended drugs are NSAIDs, as long as there is not contraindication, and in conjunction with a protective medication for the gastric mucosa, or a selective COX2 (cyclooxygenase-2) inhibitor (maximum 7 days, and do not use in cases with increased risk of a thrombotic event) [11].

Intravenous infusions of local anesthetics such as lidocaine have recently shown good results in the prevention and control of immediate postoperative pain, which it means into a lower prevalence of persistent pain after recovery. Some study protocols talk about loading doses followed by infusions of around 1–2 mg/kg/h with encouraging results [11]. There is no evidence indicating that gabapentinoids reduce or prevent CPOP, so they are not recommended [11, 13, 14]. Although no prophylactic role has been found in the use of gabapentinoids, they have been used successfully in the longterm treatment of persistent postoperative neuropathic chronic pain [15, 16].

The use of ketamine has been justified by its properties at the NMDA receptor level and its antagonism in the dorsal horn of the spinal cord. In combination with other agents, it has been shown to be effective and safe [16].

The mechanism of local anesthetics in chronic postoperative pain perhaps due to the decrease of neuronal inflammation and glial activation, avoiding chemical, structural, and functional changes [15].

The use of opioids alone for the postoperative period has not been associated with reductions in the incidence of postoperative pain; to the contrary it produces opioid-induced hyperalgesia and prolonged use after surgery. The use of opioids in multimodal therapy with NSAIDs is recommended to reduce the effects of acute inflammation induced by cyclooxygenases and the sensitization of peripheral nerve fibers [17].

Regional anesthesia and nerve blocks are perhaps one of the most useful measures for the prevention and management of CPOP. It is recommended that, when it is identified a patient with risk factors for developing CPOP, regional anesthesia can be prioritized whenever possible or, otherwise, general anesthesia using local anesthetics such as lidocaine, alpha agonists (dexmedetomidine), inhibitors of NMDA receptors (ketamine), and plexus or peripheral nerve block techniques, to maximize the analgesic effect during the intraoperative period and during the acute phase of post-surgical recovery.

#### *Chronic Postoperative Pain DOI: http://dx.doi.org/10.5772/intechopen.111878*

In abdominal surgeries, for example, improvement in acute postoperative pain and a lower incidence of CPOP have been found with the use of a transverse abdominal plane block plus placement of a continuous perfusion catheter [8]. Neck procedures under general anesthesia and a bilateral superficial cervical plexus block have been described with good results and lower levels of acute postoperative pain. This strengthens the idea that maintaining pain control during the first 24 hours after surgery reduces the risk of pain chronicity. In spinal surgery, erector spinae blockade techniques have been described for postoperative pain control with good long-term results [5].

Prevention strategies must be applied in those patients considered to be at high risk, perform a complete preoperative evaluation before and after the procedure, and develop preventive strategies establishing an appropriate therapeutic plan for each particular patient.
