**2. Pathophysiology**

Understanding the pathophysiology of post-surgical pain is crucial for the development of effective approaches to prevent and treat the CPSP. Pain is a psychological sensory experience which is caused by different factors. These factors are nociceptive, inflammatory and neuropathic pain [9]. Two main mechanisms have been described to contribute towards the development of CPSP. These are inflammation and surgical injury to major peripheral nerves [6]. Tissue cutting and handling during any surgery causes the release of sensitising, inflammatory cell mediators. These mediators are cytokines, bradykinin and prostaglandins. These inflammatory mediators activate nociceptors which demonstrate reversible plasticity. Nociceptor stimuli are carried to the dorsal horn of the spinal cord via primary afferent Aδ and C fibres as electrical impulses. Moreover, those electrical impulses will be taken to the cerebral cortex and other higher centres via the contralateral spinothalamic and spinoreticular pathways: the two main ascending pain pathways which lead to the experience of pain. This process leads to the occurrence of peripheral and central sensitisation. The peripheral sensitisation enhances pain sensitivity at the site of tissue injury. It occurs when the activation threshold of nociceptors is lowered. This type of inflammatory pain, secondary to local excitability, usually subsides once the source of the mediators subsides, as tissue healing occurs or the disease process is controlled. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of prostaglandin E2 via locally induced cyclooxygenase-2 enzymes and hence reduce peripheral sensitisation and pain. By contrast, the central sensitisation is an excitability of neurons in the central nervous system (CNS). It occurs because of enhanced pain signalling within the spinal cord in the second-order neurons due to ongoing nociceptive input which may last longer than the initial stimulus. Clinically, this manifests as wind-up, long-term potentiation, hyperalgesia and pain secondary to normally non-painful tactile stimuli (allodynia). Wind-up happens with the repeated activation of C fibres. Under normal conditions, due to the action of glutamate at N-methyl-D-aspartate (NMDA) receptors, a magnesium ion blocks the NMDA receptor. However, due to the presence of continuous painful stimuli, the response of second-order neurons to painful stimuli is amplified due to the removal of the magnesium block. This explains the role of ketamine (NMDA receptor antagonist) in reducing

described as pain which persists after a surgical procedure beyond the surgical wound-healing time. There was no consensus about the time frame which defines chronicity following surgery, and this ranged from 1 month to 1 year [3]. However, more recently, an International Association for the Study of Pain (IASP) task force has defined the period as 3 months which is consistent with the definition of chronicity in other types of chronic pain [4]. In the quest for a clearer definition, Macrae proposed a four-point definition for CPSP. CPSP becomes chronic if (1) the pain has developed as a consequence of surgery, (2) its duration is at least 2 months, (3) no other explanation exists for the pain and (4) the pain is not a continuation of

Studies have shown that the incidence of CPSP ranges from 5 to 50% [6]. Major surgical procedures such as mastectomy are associated with a higher incidence (20–50%), whereas minor procedures such as hernia repair are associated with a lower incidence (5–35%) [6]. Anatomically, the most affected sites are chest wall, breast, hip joints and iliac crest bone [1]. As any type of chronic pain, CPSP is considered as a major public health problem. It has a huge impact on the quality of life and psychological well-being. Chronic pain has been shown to affect mood, sleep and basic daily activities [7]. In severe cases, it can lead to disability. It is also associated with a heavy socio-economic burden as a result of direct costs which are related to treatment and indirect costs such as lost wages and unemployment [8]. Prevention is far more important than treatment here because of the incurable nature of CPSP and its

Hence, the aim of this chapter is to review the pathophysiology of CPSP and to explore the risk factors which contribute to its development, bearing in mind the great importance of early identification of patients who are at risk before surgery. Different modalities of treatments and interventions, which have been used in the context of prevention of CPSP, will be

Understanding the pathophysiology of post-surgical pain is crucial for the development of effective approaches to prevent and treat the CPSP. Pain is a psychological sensory experience which is caused by different factors. These factors are nociceptive, inflammatory and neuropathic pain [9]. Two main mechanisms have been described to contribute towards the development of CPSP. These are inflammation and surgical injury to major peripheral nerves [6]. Tissue cutting and handling during any surgery causes the release of sensitising, inflammatory cell mediators. These mediators are cytokines, bradykinin and prostaglandins. These inflammatory mediators activate nociceptors which demonstrate reversible plasticity. Nociceptor stimuli are carried to the dorsal horn of the spinal cord via primary afferent Aδ and C fibres as electrical impulses. Moreover, those electrical impulses will be taken to the cerebral cortex and other higher centres via the contralateral spinothalamic and spinoreticular pathways: the two main ascending pain pathways which lead to the experience of pain. This process leads to the occurrence of peripheral and central sensitisation. The peripheral

a pre-existing chronic pain condition for which the surgery was performed [5].

association with neuropathic type of pain which is always difficult to treat.

discussed.

**2. Pathophysiology**

36 Pain Management in Special Circumstances

**Figure 1.** An illustration of the two main mechanisms which contribute towards the development of CPSP (inflammation and nerve damage). The pain pathways depicted here are the ascending pain pathways [10].

or blocking wind-up. The long-term potentiation is the second-order neurons response which last longer than the initial stimulus. Hyperalgesia results from an amplified response to painful stimuli due to both long-term potentiation and lowering of the pain threshold outside of the area of inflammation [10].

Nerve damage is the second major contributor for the development of CPSP. It is very important here to try to explore the mechanisms of differentiation of neuropathic from nonneuropathic pain. In most affected patients, the pain component of CPSP is similar to pain experienced as a result of neuropathic pain [11, 12]. In patients with CPSP, neuropathic pain can occur as a consequence of spontaneous ectopic discharges from damaged nerves and nearby undamaged nerves following nerve injury. Furthermore, disinhibition of pain pathways and facilitation of pain transmission occur due to loss of inhibitory interneurons in the dorsal horn. Hypoesthesia and neuropathic pain are both caused by nerve damage. In addition, the presence of hypoesthesia in CPSP patients confirms the association between nerve damage and CPSP [11, 12]. Thoracotomy is a good example of surgeries which may lead to nerve injury. In thoracotomy, the use of a rib retractor blocks intercostal nerve conduction by 50–100% in segments close to the incision [13]. Moreover, the degree of nerve damage in thoracotomy correlates with the intensity of chronic pain [14]. In conclusion, acute and chronic pain experience is a multifactorial complex process, involving physiological, genetic and psychosocial factors. These factors contribute to the conversion of somatosensory activity into a pain experience, to the amplitude of and reaction to the sensation, and to related changes in mood and behaviour [9] (**Figure 1**).
