Exposure to noxious stimuli promotes neuroplastic changes that clinically result in hyperesthesia. Hyperesthesia is an increased sensitivity to stimulation, both painful and nonpainful. Hyperesthesia is a broad term that includes several different types of painful sensations (Merskey and Bogduk 1994):

While pain is a subjective phenomenon, the process of nociception (the encoding and processing of noxious stimuli) is an objective phenomenon that can be measured via electrophysiological testing. Electrophysiologically, hyperesthesia is observed as increased nerve fiber activity following a noxious stimulus and is termed sensitization. Sensitization occurs when receptors display a decreased activation threshold for stimulation, an increased response to suprathreshold stimuli, and spontaneous electrophysiological activity (Meyer et al. 2006). The relationship between the electrophysiological findings observed with sensitization and patients’ subjective experiences with hyperesthesia is detailed in Table 19.2.

An individual nociceptor innervates a specific area on the skin that can be measured objectively. This area of nociceptive coverage is termed the receptor field. When a nociceptor is activated by a noxious stimulus, the receptor field of that nociceptor becomes hyperalgesic, thus forming the zone of primary hyperalgesia. Neuroplastic changes primarily occurring in the PNS, or peripheral sensitization, form the zone of primary hyperalgesia. However, after a noxious stimulus, the area outside of the original receptor field can also become hyperalgesic. This surrounding area is termed the zone of secondary hyperalgesia, and it develops as a result of neuroplastic changes occurring in the CNS, or central sensitization (Fig. 19.2) (Joshi and Ogunnaike 2005).

That different mechanisms are involved in the development of the primary and secondary zones of hyperalgesia were elegantly demonstrated in an experiment by LaMotte et al. (1991). Capsaicin (a substance found in hot peppers that directly activates nociceptors producing both zones of primary and secondary hyperalgesia) was injected subcutaneously into an upper extremity that had already received a proximal nerve block, sparing the CNS of nociceptive input. By creating this interruption between the peripheral and CNS, formation of the zone of secondary hyperalgesia was entirely inhibited supporting the CNS’s integral involvement in this process (LaMotte et al. 1991).

However, during surgery, nerves not only relay nociceptive input resulting from surrounding tissue injury but also suffer injury themselves. Such injury to nervous tissue results in a specific type of pain called neuropathic pain. Characteristics of neuropathic pain can be divided into negative and positive symptoms. Negative symptoms include the sensory and motor deficits that result from the injury. Positive symptoms include any allodynia, hyperalgesia, dysesthesia, or hyperpathia at the site of the nerve injury. Hyperpathia refers to a combination of dulled sensation with increased stimulus threshold and poor localization; extreme pain with repeated stimulation that persists after the stimulation has ended; and spread of the pain from the site of stimulation. Hyperpathia appears to be unique to neuropathic pain (Devor 2006).

Peripheral sensitization and the neuropathic pain resulting from nerve injury work in conjunction to send a barrage of nociceptive signaling to the dorsal horn. This massive influx of nociceptive input, in turn, causes central sensitization to occur which further amplifies what is relayed to the brain. Higher processing then incorporates behavioral and historical components such as emotion, past memories, and psychopathological conditions into received sensory information allowing these elements to also modify how pain is perceived. Furthermore, the brain utilizes the descending tracts to exert its influence over pain processing at the level of the dorsal horn as well. Some of the mechanisms thought to be responsible for the above processes will be discussed below.

The sensitivity of the peripheral nociceptors increases with repeated stimulation. Heat sensitivity and thermal hyperalgesia are at least partly mediated by the capsaicin-sensitive vanilloid 1 receptor/ion channel complex (TRPV1). Increased intracellular calcium levels that occur as a result of repeated activation are believed to cause conformational changes increasing sensitivity of the receptor (Guenther et al. 1999). Mechanoreceptors are thought to open their associated ion channels in response to external pressure allowing cations to depolarize the nerve terminal, achieve activation threshold, and initiate an action potential. Swelling secondary to inflammation may allow these channels to more effectively open, thereby, increasing their sensitivity (Belmonte and Cervero 1996). Furthermore, some nociceptive fibers increase their receptive fields after activation, resulting in a greater response to stimulus ratio, which can produce more pain (Reeh et al. 1987; Thalhammer and LaMotte 1982).

Numerous inflammatory mediators are released upon exposure to a noxious stimulus or tissue injury including bradykinin, histamine, serotonin, adenosine derivatives, arachidonic acid metabolites, and various cytokines (Fig. 19.3). Some of these substances directly activate nociceptors further increasing their sensitivity by means of repeated stimulation. However, other mediators initiate modulatory changes to the PNS by initiating intracellular cascades leading to increased nociceptor sensitivity (Bhave and Gereau 2004; McMahon et al. 2006). Bradykinin both directly activates nociceptors as well as sensitizes the capsaicin receptor (TRPV1) via a protein kinase C pathway (Okuse 2007). Adenosine triphosphate (ATP) released from injured tissue appears to bind to its associated ion channel, P2X₃, increasing calcium influx into nociceptive nerve fibers. Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, and the chemokine IL-8 have been shown to produce mechanical and thermal hyperalgesia following injection. However, the cytokines also appear to induce peripheral sensitization via phosphorylation of nociceptive receptors by means of various intracellular kinase pathways. The prostaglandins phosphorylate the tetrodotoxin-resistant sensory neuron specific (TTX-SNS) sodium ion channel, an ion channel specific to Aδ and C-fiber nerves, via a protein kinase A (PKA) or C pathway reducing its activation threshold (Cesare et al. 1999; Khasar et al. 1999).

Additionally, several pro-inflammatory mediators have been shown to recruit a special group of nociceptive nerve fibers, termed mechanically insensitive afferents (MIAs). These fibers, as their name suggests, are normally unresponsive to mechanical stimuli and not involved in nociceptive transmission. However, upon activation, they become profoundly sensitive even to subthreshold stimuli that would normally not be noxious. This finding correlates with the hypersensitivity noted immediately following an injury (Davis et al. 1993). A cyclic AMP/PKA second messenger cascade has been implicated as the mechanism by which recruitment of MIA receptors occurs (Levy and Strassman 2002).

Inflammation also releases neurotrophins such as nerve growth factor (NGF) into the involved tissue. Neurotrophins are a family of proteins that normally act to induce survival, development, and function of neurons; however, when their concentration levels are increased they function to produce a hyperalgesic response. NGF directly causes degranulation of mast cells, and as a result provides a positive feedback loop further increasing the amount of inflammatory mediators available to induce sensitization of the peripheral nociceptors. NGF also modifies gene expression by binding to receptor tyrosine kinase A (trkA). This interaction upregulates synthesis of SNS, TRPV1 channels, substance P, calcitonin-gene-related peptide (CGRP), and bradykinin receptors further contributing to peripheral sensitization (Michael and Priestley 1999; Okuse 2007; Schaible and Richter 2004; Tate et al. 1998).

Injury to a peripheral nerve results in neuropathic pain. While healthy nerves tend to only fire after being stimulated, injured nerves often exhibit abnormal, spontaneous electrical activity termed ectopy (Fukuoka et al. 2000; Wu et al. 2001). These ectopic discharges involve not only the smaller Aδ and C-fiber nerves, but also the larger myelinated Aβ-fibers that typically encode innocuous mechanosensory information.

Ectopy develops because nerve injury induces internal changes that lead to a hyperexcitable state. As injured nerves undergo Wallerian degeneration, an inflammatory milieu develops causing increased levels of NGF to be expressed. NGF, in turn, induces changes in membrane ion channel expression resulting in both increased channel density as well as altered channel kinetics. A higher density of ion channels promotes ectopy by increasing the likelihood that depolarization occurs (Aurilio et al. 2008).

The specific role of ion channels in the development of ectopy is worth addressing. Nine subtypes of sodium ion channels have been identified and classified by their respective sensitivity or resistance to the neurotoxin, tetrodotoxin (TTX). The TTX-sensitive sodium channels become inactive quickly, resulting in burst-like signal transmissions that are most consistent with the electrical activity of ectopy. The TTX-resistant sodium channels which have slower inactivation and activation kinetics are most concentrated on the smaller Aδ and C-fiber neurons. Following a nerve injury, both TTX-sensitive and resistant channels are upregulated at the damaged site as well as along the neuron. These changes are thought to alter the membrane properties of the neuron, so that rapid firing rates (bursting ectopic discharges) are produced (Woolf and Mannion 1999). The ability of the intrinsically slower TTX-resistant channels to produce ectopic activity is believed to be a result of cascade mediated conformational changes that increase channel conductivity (Aurilio et al. 2008). In addition to the abnormal accumulation of sodium channels, there is evidence that nerve injury also promotes an increased number of calcium channels to be expressed that may contribute to ectopic activity (Xie et al. 1993). These specific phenotypic changes are important to understand as they may offer routes for targeted pharmocotherapy in the future. As will be discussed later, many of the medications used to treat neuropathic pain are nonspecific and, therefore, have many side effects. Developing agents with high affinities specific to these ion channels is a high priority in the pharmaceutical industry.

Normally, the sympathetic nervous system is not involved in nociception. However, some axons begin to express α-adrenoceptors following nerve injury, causing them to become sensitive to circulating catecholamines and norepinephrine released by postganglionic sympathetic terminals. In such a manner, the sympathetic nervous system may also become a source of nociceptive transduction, termed sympathetically maintained pain (Woolf and Mannion 1999).

Central sensitization can be viewed as having two major components. First, it serves to amplify any sensory input received at the dorsal horn. Second, it converts innocuous sensory input from non-nociceptive afferents into nociceptive transmission. In addition to CPSP, central sensitization is also involved in the development of neuropathic pain (diabetic neuropathy, postherpetic neuralgia), inflammatory pain (rheumatoid arthritis, lupus), migraine, irritable bowel syndrome (IBS), and fibromyalgia. Neurons in the dorsal horn that have been affected by central sensitization exhibit some or all of the following (Latremoliere and Woolf 2009):

When inflammatory and neuropathic pain in the periphery conduct a barrage of nociceptive signaling to the spinal cord, neuroplastic changes resulting in central sensitization begin to occur. Normal nociceptive signal conduction involves the primary afferent neuron releasing the excitatory neurotransmitters, glutamate, and aspartate into the synaptic cleft. These neurotransmitters then activate the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors on the postsynaptic membrane allowing for signal propagation to continue rostrally. However, when AMPA receptors are continuously activated, prolonged depolarization of the postsynaptic membrane occurs allowing for a normally quiescent N-methyl-d-aspartate (NMDA) channel to become activated through a loss of static inhibition by magnesium ions (Mayer et al. 1984). Activation of the NMDA receptor creates a surge in intracellular calcium which, in turn, activates numerous intracellular pathways that contribute to the maintenance of central sensitization. Together, the AMPA and NMDA receptors amplify the incoming nociceptive signal throughput in a process termed windup.

Additionally, depolarization triggers the release of neuropeptides, including substance P (SP) and CGRP, into the dorsal horn synapse. These neuropeptides activate G-protein coupled receptors, which slow postsynaptic depolarization, further allowing temporal summation and amplification of the nociceptive signal to occur. SP binds to its neurokinin 1 (NK-1) receptor activating a PKC pathway that phosphorylates the NMDA receptor. Phosphorylation of the NMDA receptor also stabilizes the receptor in its active state (Woolf and Salter 2006). These neuropeptides reside in vesicles located in the presynaptic terminal. When depolarization occurs, voltage sensitive calcium channels (VSCC) open increasing intracellular calcium concentrations, thereby allowing the vesicles to fuse with the presynaptic membrane and release their contents. Of the various types of calcium channels expressed in the nervous system, evidence suggests that the high-threshold N-type channels located in the superficial Rexed laminae (discussed further below) are most important to the development of central sensitization (Fig. 19.4) (Aurilio et al. 2008).

Synaptic connections at the dorsal horn are not permanent, and their rearrangement may explain how normally innocuous input from mechanosensory Aβ-fibers is perceived as painful after central sensitization has occurred. Typically, nociceptive fibers synapse superficially in the dorsal horn at Rexed laminae I and II while mechanosensitive fibers synapse at the deeper Rexed laminae. Aβ-fibers do have dendritic extensions to nociceptors in the more superficial laminae. Normally signals via these extensions are thought to be inhibited by interneurons. One theory of allodynia is that a loss of this inhibition occurs allowing for non-noxious stimuli to be miscoded as a nociceptive signal (Todd 2010 #817). Furthermore, following central sensitization the synaptic locations of the Aβ-fibers migrate superficially so that they activate secondary neurons of the nociceptive pathway (Schaible and Richter 2004). Such rearrangement of synaptic connections at the dorsal horn may extend rostrally or caudally one or more levels contiguously.

Other factors may also have roles in the development of secondary hyperalgesia. For example, tissue damage itself, particularly to low-threshold non-noxious peripheral receptors, may also facilitate this process. The normal activity of these innocuous receptors partially inhibits the conduction of pain signals upon activation of nociceptors (Bini et al. 1984). Therefore, loss of this innocuous transmission may result in a central disinhibition of nociceptor input (Meyer et al. 2006). As will be discussed in the next section, supraspinal influence at the level of the dorsal horn is also very much involved in the development of central sensitization.

The ability of the brain to modulate nociceptive signaling at the level of the dorsal horn is dependent on two structures: the PAG and the rostral ventromedial medulla (RVM). The PAG is located in the midbrain and receives direct inputs from numerous higher structures including the anterior cingulate, insular cortex, and amygdala. Indirectly, structures such as the nucleus accumbens and lateral hypothalamus project to the PAG. The PAG also interacts with its neighboring regions, the nucleus cuneiformis, the reticular formation, the locus coeruleus, and other brainstem catecholaminergic nuclei. Finally, the PAG receives direct projections from lamina I nociceptive neurons.

The PAG exerts its influence over nociceptive processing at the dorsal horn via its interaction with the RVM. The RVM is located in the medulla and includes the midline nucleus raphe magnus and the adjacent reticular formation that lies ventral to the nucleus reticularis gigantocellularis. The major descending tracts to the dorsal horn of the spinal cord initiate from the RVM. Three classes of neurons that travel from the RVM to the dorsal horn have been identified: on-cells, off-cells, and neutral cells. These neurons are found throughout the RVM and are not anatomically separable; they have instead been classified based on their activity responses to a noxious stimulus. Off-cells display an abrupt pause in ongoing activity immediately following a noxious stimulus and are believed to contribute to the inhibitory influences of the RVM on the dorsal horn. On-cells display a burst of activity immediately following a noxious stimulus and are believed to contribute to the facilitatory influences of the RVM on the dorsal horn. Neutral cells show no change in activity related to noxious stimuli (Fields et al. 2006 #810).

While the PAG-RVM descending modulatory system is most known for the attenuating effects it has on pain, more recently there has been growing evidence that it may have significant roles in facilitating chronic pain states as well. Low-intensity electrical stimulation of the RVM or direct injection of the neurotransmitter glutamate has been shown to increase spinal nociception. These facilitatory influences appear to involve an anatomically separate descending projection system in the ventrolateral funiculi and to be mediated by spinal serotonin and cholecystokinin receptors. Furthermore, secondary hyperalgesia following certain pain states such as mustard oil-induced sensitization and neuropathic pain after spinal nerve ligation can be attenuated by inactivation of the RVM. NMDA, neurontensin (NT), and nitric oxide (NO⁻) receptors in the RVM appear to be involved in these processes. An illustration of this proposed spinobulbospinal pathway and its role in secondary hyperalgesia is presented in Fig. 19.5 (Urban 1999 #814).

In its healthy state, the basal tone of this processing appears to be mostly inhibitory to prevent spontaneous nociceptive signals from occurring in the absence of actual noxious stimuli or tissue injury. This inhibitory state does not appear to opioid driven given the fact that intrathecal injection of the opioid inhibitor naloxone does not cause hyperalgesia. Serotonin has been proposed as partially responsible for the tonic inhibitory state. Supporting this hypothesis are the facts that the RVM is the exclusive source of serotonin in the dorsal horn, serotonergic RVM neurons continuously slowly release serotonin into the dorsal horn, and intrathecal administration of serotonin antagonists has been found to reduce the effectiveness of the RVM to produce analgesia. However, as mentioned above at least one serotonin receptor (5-HT₃) appears to also be involved in facilitating certain pain states, suggesting that serotonin probably plays a more complex role in modulating pain (Fields et al. 2006 #810).

Certain behavioral states have consistently been shown to alter pain perception. Studies evaluating the relationship of attention and pain have reliably demonstrated that when subjects are distracted they report less pain (Levine et al. 1982 #824; Miron et al. 1989 #826). This is obviously a difficult association to unravel because pain itself is an attention-demanding phenomenon. In fact, a decreased ability to distract attention away from pain may be a feature common to chronic pain patients (Grisart and Plaghki 1999 #827).

The pathways and mechanisms behind how attention modifies pain perception are still incompletely understood. Neurophysiological studies have shown that modulation from attentional changes occurs even at the level of the dorsal horn (Villemure and Bushnell 2002 #822). The aid of functional MRI (fMRI) has also demonstrated that attention influences many of the same brain regions involved with pain processing. Tracey et al. observed that PAG activity was significantly increased when subjects were distracted from pain (Tracey et al. 2002 #829). Other areas of the brain involved in attention and pain appear to be the secondary somatosensory cortex (S2), anterior cingulate cortex, and insula (Sawamoto et al. 2000 #836).

The inability of chronic pain patients to distract themselves from the experience of pain has been proposed as one driving maladaptive behavior. Normally, the pain associated with repeated exposure to a noxious stimulus diminishes over time in a process termed habituation or a time-dependent decline of vigilance. The same areas of the brain thought to be crucial for maintaining vigilance are also involved in focusing attention to pain. Therefore, patients with chronic pain may exhibit a “hypervigilant” state in which they fail to return to their basal sensory states and disengage pain (Lorenz and Tracey 2009 #838).

Another central concept to understanding the relationship between behavior and pain is that of placebo and nocebo behavior (see also Pollo and Benedetti 2011). A placebo effect is the concept that the expectation of pain relief is able to independently provide analgesia. Mechanistically, this process is thought to be driven by the prefrontal cortex via the PAG-RVM descending modulatory system. In contrast to a placebo effect, a nocebo effect is that of increased pain secondary to a negative expectation of pain. fMRI has associated the S2 and posterior insula with the nocebo effect, and there is evidence that the hyperalgesia is mediated by spinal cholecystokinin. Such maladaptive behaviors such as anxiety, catastrophizing, and excessive fear of injury are believed to evoke nocebo phenomenon. Key brain regions and how they are thought to relate to behavior and pain can be seen in Fig. 19.6 (Lorenz and Tracey 2009 #838).

Ample evidence exists demonstrating that a given surgical approach can influence the development of CPSP. The major cause of CPSP is thought to be nerve injury, either directly from the surgical insult or from other consequences such as inflammation or scar tissue. Thus, new surgical techniques have been designed to reduce the overall amount of tissue and nerve injury, and in doing so, to help prevent CPSP. Laparoscopically assisted surgery has been shown to result in decreased long-term post-surgical pain for both hernia repair and cholecystectomy (Grant et al. 2004; Stiff et al. 1994). Nerve sparing approaches for both mastectomy and thoracotomy have also reduced post-surgical morbidity (Cerfolio et al. 2003; Jung et al. 2003). Surgical techniques such as sentinel lymph node biopsy, which were developed to reduce the number of axillary radical dissections performed, have also decreased the incidence of chronic postmastectomy pain (Sclafani and Baron 2008).

An increased risk of CPSP has been associated with a surgical duration of greater than 3 h (Peters et al. 2007). This is probably because a longer, more complicated procedure is likely to involve greater amounts of tissue injury and nerve damage. Furthermore, the incidence of CPSP has been observed to be decreased when the surgery is performed at a high vs. low volume surgical unit (Tasmuth et al. 1999). This finding is commensurate with several studies reporting a favorable association between high procedural volume centers and reduced surgical morbidity (Battaglia et al. 2006; Rectenwald and Upchurch 2007; Wilt et al. 2008).

Concomitant treatments may also increase the incidence of CPSP. Chronic pain has been reported to be increased following amputation and mastectomy when performed in close conjunction with radiation or chemotherapy (Gulluoglu et al. 2006; Smith and Thompson 1995). Whether such therapeutic regimens contribute to pain following other types of surgery is still uncertain; however, the potential for radiation or chemotherapy alone to cause neuropathic pain is also well documented (Argyriou et al. 2008; Forman 1990).

Acute pain appears to correlate with the development of chronic pain. This relationship exists for acute pain in both the preoperative and postoperative settings. Amputees with severe preoperative pain are more likely to develop intense phantom limb pain than those who report no or only mild preoperative pain (Jensen et al. 1985; Nikolajsen et al. 1997). Similarly, severe postoperative pain has been shown to be an independent risk factor for the development of CPSP after thoracotomy (Katz et al. 1996), mastectomy (Poleshuck et al. 2006), herniorrhaphy (Aasvang and Kehlet 2005), and Cesarean section (Nikolajsen et al. 2004). These findings are consistent with the idea that neuroplastic changes begin in the acute setting.

While the true gender prevalence of chronic pain remains debated, women report more severe pain, more frequent bouts of pain, and more anatomically diffuse pain compared to men (Hurley and Adams 2008, see also Keogh 2011). This tendency for the female population to report greater pain has been observed with postthoracotomy pain (Gotoda et al. 2001). Younger age may also predispose the development of CPSP. Poleshuck et al. reported that the probability of developing chronic pain after breast surgery decreased 5% for each additional year of age (Poleshuck et al. 2006). This relationship may be partly explained by younger patients tending to have more aggressive and advanced disease, therefore, requiring more extensive surgery (Kroman et al. 2000).

Conflicting evidence exists regarding psychological predictors for CPSP. Harden et al. found that preoperative anxiety was related to the development of complex regional pain syndrome (CRPS) following total knee arthroplasty (Harden et al. 2003). However, in another study by Katz et al., no relationship was found between depression and anxiety and postthoracotomy pain (Katz et al. 1996). It should be noted, however, that Katz’s study questioned patients 1 day prior to surgery, and this timing may have falsely elevated the number of patients expressing symptoms of both depression and anxiety. Traits of neuroticism and an introverted personality have been found to be related to postcholecystectomy pain (Borly et al. 1999). A recent review of the literature by Hinrichs-Rocker et al. (2009) observed that depression, psychological vulnerability, and stress to be the most reliable psychological predictors of CPSP currently known.

Pain catastrophizing may also be related to the development of CPSP. Pain catastrophizing is defined as an exaggerated negative orientation to aversive stimuli that involves rumination about painful sensations, magnification of the threat value of the painful stimulus, and perceived inability to control pain (Granot and Ferber 2005). These inappropriate pain behaviors are generally considered maladaptive coping strategies, and as such, often result in increased anxiety levels. Pain catastrophizing has been demonstrated to be a risk factor for increased chronic pain in rheumatoid arthritis patients (Keefe et al. 1989). Currently available studies evaluating the role of catastrophizing in CPSP, however, are conflicting. While catastrophizing has been shown to predict acute post-­surgical pain intensity (Pavlin et al. 2005), other studies have been unable to establish such a correlation with CPSP, despite the fact that severe acute post-surgical pain is itself a risk factor for CPSP (Hanley et al. 2004; Peters et al. 2007). In fact, more frequent catastrophizing 1 month postoperatively was found to be associated with greater improvement in the pain score at 2 years postoperatively. This finding may be due to this study having only evaluated the absolute change in pain scores as opposed to actual pain scores. Therefore, a patient with frequent catastrophizing at 1 month may have a higher overall pain score, thereby giving that patient more room to improve. However, one alternative explanation provided by the authors was that early catastrophizing has a paradoxically beneficial role by prompting earlier recognition and treatment.

A patient’s social environment as a predictor of CPSP has also been assessed. One study investigating the risk factors for phantom limb pain found lack of social support to be a major predictor (Jensen et al. 2002). This finding was supported in a subsequent study evaluating the incidence of postamputation pain (Hanley et al. 2004). Solicitous behavior, in which family members (often unknowingly) reinforce a patient’s pain behaviors, may also be a risk factor for developing CPSP (Katz and Seltzer 2009).

Finally, there may be genetic predisposition to the development of chronic neuropathic pain that increases the likelihood of CPSP. The link has been demonstrated in animal studies, in which specific strains of mice are more likely to develop neuropathic pain after nerve injury (Seltzer et al. 2001). There is also evidence that patients with CPSP are more likely to have other functional pain syndromes such as IBS, temporomandibular joint disorder (TMJD), migraine, and fibromyalgia (Macrae 2008). Yarnitsky et al. tested patients’ diffuse noxious inhibitor control (DNIC), a marker of one’s overall endogenous analgesia system, prior to undergoing thoracotomy. Although the level of DNIC did not correlate with acute post-surgical pain, it was directly related to the development of chronic postthoracotomy pain. This finding suggests that not only is there likely a genetic predisposition to developing CPSP, but also that the mechanisms of acute and CPSP are most likely distinct (Yarnitsky et al. 2008).